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• W2897524551 abstract "•An iPSC-based neuronal model of MSA is described•Mitochondria are dysfunctional in MSA neurons•Autophagic machinery is impaired in MSA neurons Multiple system atrophy (MSA) is a progressive neurodegenerative disease that affects several areas of the CNS, whose pathogenesis is still widely unclear and for which an effective treatment is lacking. We have generated induced pluripotent stem cell-derived dopaminergic neurons from four MSA patients and four healthy controls and from two monozygotic twins discordant for the disease. In this model, we have demonstrated an aberrant autophagic flow and a mitochondrial dysregulation involving respiratory chain activity, mitochondrial content, and CoQ10 biosynthesis. These defective mechanisms may contribute to the onset of the disease, representing potential therapeutic targets. Multiple system atrophy (MSA) is a progressive neurodegenerative disease that affects several areas of the CNS, whose pathogenesis is still widely unclear and for which an effective treatment is lacking. We have generated induced pluripotent stem cell-derived dopaminergic neurons from four MSA patients and four healthy controls and from two monozygotic twins discordant for the disease. In this model, we have demonstrated an aberrant autophagic flow and a mitochondrial dysregulation involving respiratory chain activity, mitochondrial content, and CoQ10 biosynthesis. These defective mechanisms may contribute to the onset of the disease, representing potential therapeutic targets. Multiple system atrophy (MSA) is a severe and progressive neurodegenerative disease. Parkinsonism, cerebellar ataxia, dysautonomia, and pyramidal features are the main clinical hallmarks. According to the predominant symptomatology at onset, either parkinsonian or cerebellar, two different subtypes of the disease can be distinguished: MSA-P and MSA-C, respectively (Fanciulli and Wenning, 2015Fanciulli A. Wenning G.K. Multiple-system atrophy.N. Engl. J. Med. 2015; 372: 249-263Crossref PubMed Scopus (282) Google Scholar). Although many preclinical and clinical trials are in progress (Valera et al., 2016Valera E. Monzio Compagnoni G. Masliah E. Review: novel treatment strategies targeting alpha-synuclein in multiple system atrophy as a model of synucleinopathy.Neuropathol. Appl. Neurobiol. 2016; 42: 95-106Crossref PubMed Scopus (21) Google Scholar), an effective treatment is still lacking. Neuropathologically, MSA is characterized by atrophy mainly in the putamen in MSA-P and in the cerebellum, middle cerebellar peduncles, and pontine basis in MSA-C. α-Synuclein accumulation is the neuropathological hallmark of the disease. Differently from other α-synucleinopathies, it occurs mainly in oligodendrocytes in the form of glial cytoplasmic inclusions. However, α-synuclein aggregates can be detected also in glial nuclei, neuronal cytoplasm, neuronal nuclei, and astroglial cytoplasm. Moreover, astrogliosis and microglial activation are common findings in MSA. Despite the peculiarity of oligodendroglial involvement, neuronal systems are strongly affected. A prominent degeneration of striatonigral pathway (both striatal medium spiny neurons and substantia nigra dopaminergic neurons) is observed in MSA-P. MSA-C displays a remarkable degeneration of Purkinje cells and cerebellopontine fibers; however, substantia nigra is also affected (Jellinger, 2014Jellinger K.A. Neuropathology of multiple system atrophy: new thoughts about pathogenesis.Mov. Disord. 2014; 29: 1720-1741Crossref PubMed Scopus (96) Google Scholar). The role of mitochondrial dysfunction in the onset and progression of MSA has been debated. The most direct evidence supporting this scenario is the report of mutations in COQ2, a gene involved in the synthesis of CoenzymeQ10 (CoQ10), in familial and sporadic MSA cases (Multiple-System Atrophy Research Collaboration, 2013Multiple-System Atrophy Research CollaborationMutations in COQ2 in familial and sporadic multiple-system atrophy.N. Engl. J. Med. 2013; 369: 233-244Crossref PubMed Scopus (191) Google Scholar), but this finding has not been replicated in independent MSA cohorts (Sharma et al., 2014Sharma M. Wenning G. Krüger R. European Multiple-System Atrophy Study GroupMutant COQ2 in multiple-system atrophy.N. Engl. J. Med. 2014; 371: 80-81Crossref PubMed Scopus (42) Google Scholar, Schottlaender et al., 2014Schottlaender L.V. Houlden H. Multiple-System Atrophy (MSA) Brain Bank CollaborationMutant COQ2 in multiple-system atrophy.N. Engl. J. Med. 2014; 371: 81Crossref PubMed Google Scholar, Ronchi et al., 2016Ronchi D. Di Biase E. Franco G. Melzi V. Del Sorbo F. Elia A. Barzaghi C. Garavaglia B. Bergamini C. Fato R. et al.Mutational analysis of COQ2 in patients with MSA in Italy.Neurobiol. Aging. 2016; 45: 213.e1-213.e2Abstract Full Text Full Text PDF Scopus (13) Google Scholar). The assessment of the activity of respiratory chain complexes in autoptic substantia nigra and platelets of patients has not provided significant results (Gu et al., 1997Gu M. Gash M.T. Cooper J.M. Wenning G.K. Daniel S.E. Quinn N.P. Marsden C.D. Schapira A.H. Mitochondrial respiratory chain function in multiple system atrophy.Mov. Disord. 1997; 12: 418-422Crossref PubMed Scopus (67) Google Scholar). Two independent groups have recently described a reduction of CoQ10 levels selectively in cerebellum of MSA patients without mutations in COQ2, but not in striatum, frontal cortex, or occipital cortex (Schottlaender et al., 2016Schottlaender L.V. Bettencourt C. Kiely A.P. Chalasani A. Neergheen V. Holton J.L. Hargreaves I. Houlden H. Coenzyme Q10 levels are decreased in the cerebellum of multiple-system atrophy patients.PLoS One. 2016; 11: e0149557Crossref PubMed Scopus (30) Google Scholar, Barca et al., 2016Barca E. Kleiner G. Tang G. Ziosi M. Tadesse S. Masliah E. Louis E.D. Faust P. Kang U.J. Torres J. et al.Decreased coenzyme Q10 levels in multiple system atrophy cerebellum.J. Neuropathol. Exp. Neurol. 2016; 75: 663-672Crossref PubMed Scopus (28) Google Scholar). Nevertheless, the activity level of complexes I + III and II + III, closely related to CoQ10, have not shown significant differences. Furthermore, the amount of two enzymes involved in CoQ10 synthesis (PDSS1 and COQ5) has been found to be reduced in MSA brains (Barca et al., 2016Barca E. Kleiner G. Tang G. Ziosi M. Tadesse S. Masliah E. Louis E.D. Faust P. Kang U.J. Torres J. et al.Decreased coenzyme Q10 levels in multiple system atrophy cerebellum.J. Neuropathol. Exp. Neurol. 2016; 75: 663-672Crossref PubMed Scopus (28) Google Scholar). Upregulation of autophagy is another feature that has been observed in autoptic MSA samples (Schwarz et al., 2012Schwarz L. Goldbaum O. Bergmann M. Probst-Cousin S. Richter-Landsberg C. Involvement of macroautophagy in multiple system atrophy and protein aggregate formation in oligodendrocytes.J. Mol. Neurosci. 2012; 47: 256-266Crossref PubMed Scopus (55) Google Scholar, Tanji et al., 2013Tanji K. Odagiri S. Maruyama A. Mori F. Kakita A. Takahashi H. Wakabayashi K. Alteration of autophagosomal proteins in the brain of multiple system atrophy.Neurobiol. Dis. 2013; 49: 190-198Crossref PubMed Scopus (36) Google Scholar). Few models of MSA have been developed, mainly represented by transgenic mice with overexpression of human α-synuclein in oligodendrocytes (Shults et al., 2005Shults C.W. Rockenstein E. Crews L. Adame A. Mante M. Larrea G. Hashimoto M. Song D. Iwatsubo T. Tsuboi K. Masliah E. Neurological and neurodegenerative alterations in a transgenic mouse model expressing human alpha-synuclein under oligodendrocyte promoter: implications for multiple system atrophy.J. Neurosci. 2005; 25: 10689-10699Crossref PubMed Scopus (176) Google Scholar, Kahle et al., 2002Kahle P.J. Neumann M. Ozmen L. Muller V. Jacobsen H. Spooren W. Fuss B. Mallon B. Macklin W.B. Fujiwara H. et al.Hyperphosphorylation and insolubility of alpha-synuclein in transgenic mouse oligodendrocytes.EMBO Rep. 2002; 3: 583-588Crossref PubMed Scopus (237) Google Scholar, Yazawa et al., 2005Yazawa I. Giasson B.I. Sasaki R. Zhang B. Joyce S. Uryu K. Trojanowski J.Q. Lee V.M. Mouse model of multiple system atrophy alpha-synuclein expression in oligodendrocytes causes glial and neuronal degeneration.Neuron. 2005; 45: 847-859Abstract Full Text Full Text PDF PubMed Scopus (230) Google Scholar). Although these models have allowed dissection of some important aspects of MSA pathogenesis, they cannot recapitulate all the aspects of human pathology. Indeed, α-synuclein is artificially overexpressed and the role of other cells, including neurons, can be underestimated. Induced pluripotent stem cells (iPSCs), whose generation has been described only a decade ago (Takahashi and Yamanaka, 2006Takahashi K. Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors.Cell. 2006; 126: 663-676Abstract Full Text Full Text PDF PubMed Scopus (16795) Google Scholar), have been used to model several neurodegenerative disorders, such as Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis (Ross and Akimov, 2014Ross C.A. Akimov S.S. Human-induced pluripotent stem cells: potential for neurodegenerative diseases.Hum. Mol. Genet. 2014; 23: R17-R26Crossref PubMed Scopus (80) Google Scholar). Both idiopathic and familial (LRRK2, PINK1, PRKN, GBA, and SNCA) Parkinson's disease has been modeled as well (Torrent et al., 2015Torrent R. De Angelis Rigotti F. Dell'Era P. Memo M. Raya A. Consiglio A. Using iPS cells toward the understanding of Parkinson's disease.J. Clin. Med. 2015; 4: 548-566Crossref PubMed Google Scholar). A single iPSC-based study has been reported so far, aiming to differentiate MSA-derived iPSCs toward oligodendrocytes (Djelloul et al., 2015Djelloul M. Holmqvist S. Boza-Serrano A. Azevedo C. Yeung M.S. Goldwurm S. Frisén J. Deierborg T. Roybon L. Alpha-synuclein expression in the oligodendrocyte lineage: an in vitro and in vivo study using rodent and human models.Stem Cell Reports. 2015; 5: 174-184Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar). These experiments have provided evidence for α-synuclein expression in differentiating oligodendrocytes. However, this study has not explored the cellular and molecular pathogenic events in MSA neurons. In this perspective, we have established an iPSC-based neuronal in vitro model of MSA and have demonstrated mitochondrial dysregulation and impaired autophagy in patients' neurons that can contribute to pathogenesis. We generated iPSCs from skin fibroblasts of four patients affected with MSA (two MSA-P and two MSA-C) and five unaffected subjects, including the healthy monozygotic twin of one of the MSA-C patients (MSA-C1/AT). Diagnosis of probable MSA was performed according to widely accepted clinical criteria (Gilman et al., 2008Gilman S. Wenning G.K. Low P.A. Brooks D.J. Mathias C.J. Trojanowski J.Q. Wood N.W. Colosimo C. Dürr A. Fowler C.J. et al.Second consensus statement on the diagnosis of multiple system atrophy.Neurology. 2008; 71: 670-676Crossref PubMed Scopus (1798) Google Scholar). The main clinical features of the subjects are described in Table 1.Table 1Main Clinical Features of Subjects Involved in the StudyPatient CodeDiagnosisSexAge at Biopsy (Years)Age at Onset (Years)Familial HistoryP1MSA-PF7868noP2MSA-PM5552noC1 (AT)MSA-CF5955noC2MSA-CF6056noCTR1–M24–noCTR2–F60–noCTR3–M68–noCTR4–F80–noUT–F59–no Open table in a new tab All subjects were negative for mutations in genes commonly involved in Parkinson’s disease (LRRK2, GBA, and SNCA), multiplication of SNCA gene, and ATXN1, ATXN2, ATXN3, ATXN8, and PPP2R2B pathological repeats. Genomic rearrangements were excluded by CGH array performed on DNA from blood. As previously reported (Ronchi et al., 2016Ronchi D. Di Biase E. Franco G. Melzi V. Del Sorbo F. Elia A. Barzaghi C. Garavaglia B. Bergamini C. Fato R. et al.Mutational analysis of COQ2 in patients with MSA in Italy.Neurobiol. Aging. 2016; 45: 213.e1-213.e2Abstract Full Text Full Text PDF Scopus (13) Google Scholar), a homozygous variant in COQ2 gene (p.A43G) was found in one patient (MSA-C2). However, the mutation did not affect respiratory chain activity in muscle and CoQ10 amount in muscle and fibroblasts. iPSCs were generated from skin fibroblasts through a non-integrating reprogramming method based on the expression of factors OCT4, SOX2, KLF4, and C-MYC. Different clones of iPSCs were isolated and expanded. Immunocytochemistry demonstrated that most of the cells in all iPSC clones expressed the pluripotency markers SSEA-4 and OCT4 (Figure 1A). The karyotype of all the lines was assessed to exclude genetic rearrangements due to the reprogramming process (Figure 1B). RT-PCR analysis showed a high expression of the pluripotency markers OCT4 and NANOG in all iPSC lines compared with fibroblasts (Figure 1C). All iPSC lines were differentiated toward dopaminergic neurons through an already described protocol (Zhang et al., 2014Zhang P. Xia N. Reijo Pera R.A. Directed dopaminergic neuron differentiation from human pluripotent stem cells.J. Vis. Exp. 2014; : 51737PubMed Google Scholar), which allows the generation of tyrosine hydroxylase (TH)-positive neurons with high efficiency. At 35 days in vitro (DIV) most of the cells were positive for the neuronal marker TUJ1 and more than 55% of TUJ1-positive cells were also positive for the catecholaminergic marker TH, as assessed by immunocytochemistry (Figure 2A and Table S1). At 50 DIV the majority of differentiated cells was also positive for the neuronal marker MAP2 (Figure 2B and Table S1). These values are in line with the ones described in the applied protocol. RT-PCR was performed at 35 DIV. All the cell lines highly expressed the markers TUBB3, MAP2, and TH compared with fibroblasts and iPSCs (Figure 2C). TUJ1 expression at 35 DIV was confirmed by a robust signal detected at western blot, which was absent in fibroblasts (Figure 2D). Western blot also demonstrated a high amount of tyrosine hydroxylase in all neuronal lines at 70 DIV (Figure S1A). To verify a mature neuronal identity, we performed electrophysiology. At 56 DIV evoked action potentials and spontaneous firing activity in neurons were detected (Figures 3A and 3B ), and inward and outward currents were recorded (Figure 3C). Post-synaptic activity was evaluated at 70 DIV, but spontaneous post-synaptic potentials were rarely observed with the exception of low amplitude spikes (Figure 3D). To assess the full maturation of neurons, we evaluated three lines of iPSC-derived neurons (MSA-P2, MSA-C2, and CTR1) for sphingolipid composition (Schöndorf et al., 2014Schöndorf D.C. Aureli M. McAllister F.E. Hindley C.J. Mayer F. Schmid B. Sardi S.P. Valsecchi M. Hoffmann S. Schwarz L.K. et al.iPSC-derived neurons from GBA1-associated Parkinson's disease patients show autophagic defects and impaired calcium homeostasis.Nat. Commun. 2014; 5: 4028Crossref PubMed Scopus (268) Google Scholar) at two differentiation steps, 35 DIV and 70 DIV (Figure 3E; Tables S2 and S3). Differentiated iPSCs contained all the polysialogangliosides found in the CNS. The radioactivity associated with gangliosides ranged from 16% to 22% of the total radioactivity associated with the sphingolipid content, and quantitatively was in the range from 1.5 to 2.7 nCi/mg of cellular protein. These data resemble those obtained from rat granule cells differentiating in culture (Prinetti et al., 2001Prinetti A. Chigorno V. Prioni S. Loberto N. Marano N. Tettamanti G. Sonnino S. Changes in the lipid turnover, composition, and organization, as sphingolipid-enriched membrane domains, in rat cerebellar granule cells developing in vitro.J. Biol. Chem. 2001; 276: 21136-21145Crossref PubMed Scopus (141) Google Scholar) and suggest that the analyzed cell population is enriched with fully differentiated neurons. To investigate the presence of defects in neuronal maturation and survival in patients, we assessed the level of specific proteins through western blot: synapsin I, synapsin III, synaptophysin (synaptic markers), and TAU (neurite protein) (Figures 4A, 4B , and S1B). At 70 DIV MSA neurons showed a significant lower level of TAU (p < 0.001) and synapsin I (p < 0.001) compared with controls, and the twins showed a similar behavior. Data at 70 DIV were also normalized for the neuronal marker TUJ1, confirming TAU reduction in patients (p < 0.01) (Figure S1C). qPCR demonstrated that the observed Tau protein reduction in MSA was not due to low MAPT mRNA expression levels (Figure S1D). α-Synuclein protein amount was not different between patients and controls (Figure 4C). The level of autophagy-related proteins was investigated before and after treatment with bafilomycin A1, a V-ATPase inhibitor which causes block of the fusion between the autophagosome and the lysosome (Klionsky et al., 2012Klionsky D.J. Abdalla F.C. Abeliovich H. Abraham R.T. Acevedo-Arozena A. Adeli K. Agholme L. Agnello M. Agostinis P. Aguirre-Ghiso J.A. et al.Guidelines for the use and interpretation of assays for monitoring autophagy.Autophagy. 2012; 8: 445-544Crossref PubMed Scopus (2609) Google Scholar). LC3-II amount was significantly higher in patients than in controls (p < 0.05), suggesting an autophagic activation. Furthermore, the autophagic flux proved to be more efficient in controls, as demonstrated by a significant difference in the ratio between LC3-II level after bafilomycin treatment and LC3-II basal level (p < 0.05). Interestingly, the two twins discordant for the disease showed a similar behavior (Figure 5A). Decreased LAMP1 and increased p62 were detected in patients (Figure S2A). In addition, we assessed the activity of five lysosomal enzymes (GBA1, β-galactosidase, β-hexosaminidase, α-mannosidase, β-mannosidase) in neurons. GBA1, β-galactosidase, and β-hexosaminidase were similar in patients and controls. By contrast, the activity of α-mannosidase and β-mannosidase proved to be reduced in patients (p < 0.001 for both the enzymes). This finding was confirmed in the two twins (Figure 5B). The activity of respiratory chain complexes I, II, I + III, II + III, and IV was investigated through spectrophotometric analyses. Values were normalized for the activity of citrate synthase (CS), a matrix enzyme index of mitochondrial mass. The activity level of complexes II and II + III was significantly lower in patients (p < 0.01 and p < 0.001, respectively) and a trend of reduction was observed for complexes I + III. A similar behavior was observed in the twins (Figure 6A). To assess whether the mitochondrial respiratory enzyme activity reduction was associated with reduced protein steady-state levels, we assessed the amounts of complex I, complex II (SDHA, SDHB), complex III, complex IV, and complex V by western blot and normalized them for the mitochondrial structural protein TOMM20. The amount of complexes was not reduced, indicating that the impaired activity was not related to the level of mitochondrial protein. Interestingly, complex II (both SDHA and SDHB subunits) and complex III were significantly more expressed in patients, suggesting a possible compensatory mechanism (Figures 6B and 6C). To explore the reason for decreased activity of complexes II + III in MSA, we assessed the amount of CoQ10 and of the enzymes involved in CoQ10 synthesis (PDSS1, PDSS2, COQ2, COQ4, COQ5, COQ6, COQ7, ADCK3/COQ8A, and COQ9). CoQ10 levels were similar between the groups, while an increased amount of CoQ10 biosynthetic enzymes (PDSS1, PDSS2, COQ4, and ADCK3/COQ8A) was detected in patients (Figures 6F, 6G, and S2B). To assess whether the higher amount of mitochondrial respiratory enzymes and CoQ10 biosynthetic enzyme levels was also accompanied by increased mitochondrial mass, we evaluated the level of TOMM20, an outer membrane mitochondrial structural protein, which was significantly higher in patients (p < 0.05) (Figures 6B and 6D). Confirming this finding, mitochondrial DNA content, a reliable indicator of mitochondrial mass, was significantly upregulated in MSA (p < 0.01) (Figure 6E). Interestingly, autophagy- and mitochondria-related findings were more pronounced in MSA-P, as demonstrated by reanalyzing MSA-P and MSA-C groups separately (Figures S3 and S4). The present study aimed to evaluate the pathogenic mechanisms of MSA, exploiting the promising model of iPSCs, so far unexplored in this disease. The efficiency of dopaminergic differentiation was demonstrated by the high expression of markers of mature neuronal identity, the analysis of sphingolipid composition, and electrophysiological records. At 70 DIV TAU and synapsin I were markedly decreased in MSA neurons, likely suggesting loss of neurites. Interestingly, only synapsin I was reduced, whereas synapsin III, described to be highly expressed in extrasynaptic regions (Porton et al., 2011Porton B. Wetsel W.C. Kao H.T. Synapsin III: role in neuronal plasticity and disease.Semin. Cell Dev. Biol. 2011; 22: 416-424Crossref PubMed Scopus (25) Google Scholar), did not display changes. No differences were observed in the levels of TAU and synapsin I between patients and controls at 35 DIV, suggesting neuronal damage possibly correlated with aging. Impairment of two pathways, autophagy and mitochondrial functioning, was observed in MSA neurons in this study. Autophagic impairment has been studied in depth in α-synucleinopathies (Xilouri et al., 2016Xilouri M. Brekk O.R. Stefanis L. Autophagy and alpha-synuclein: relevance to Parkinson's disease and related synucleopathies.Mov. Disord. 2016; 31: 178-192Crossref PubMed Scopus (124) Google Scholar). A possible involvement of this pathway has been described both in brains of patients with Lewy body disease and in mouse models (Klucken et al., 2012Klucken J. Poehler A.M. Ebrahimi-Fakhari D. Schneider J. Nuber S. Rockenstein E. Schlötzer-Schrehardt U. Hyman B.T. McLean P.J. Masliah E. Winkler J. Alpha-synuclein aggregation involves a bafilomycin A 1-sensitive autophagy pathway.Autophagy. 2012; 8: 754-766Crossref PubMed Scopus (85) Google Scholar, Yu et al., 2009Yu W.H. Dorado B. Figueroa H.Y. Wang L. Planel E. Cookson M.R. Clark L.N. Duff K.E. Metabolic activity determines efficacy of macroautophagic clearance of pathological oligomeric alpha-synuclein.Am. J. Pathol. 2009; 175: 736-747Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar, Crews et al., 2010Crews L. Spencer B. Desplats P. Patrick C. Paulino A. Rockenstein E. Hansen L. Adame A. Galasko D. Masliah E. Selective molecular alterations in the autophagy pathway in patients with Lewy body disease and in models of alpha-synucleinopathy.PLoS One. 2010; 5: e9313Crossref PubMed Scopus (241) Google Scholar). Furthermore, an upregulation of autophagy has been described in MSA (Schwarz et al., 2012Schwarz L. Goldbaum O. Bergmann M. Probst-Cousin S. Richter-Landsberg C. Involvement of macroautophagy in multiple system atrophy and protein aggregate formation in oligodendrocytes.J. Mol. Neurosci. 2012; 47: 256-266Crossref PubMed Scopus (55) Google Scholar, Tanji et al., 2013Tanji K. Odagiri S. Maruyama A. Mori F. Kakita A. Takahashi H. Wakabayashi K. Alteration of autophagosomal proteins in the brain of multiple system atrophy.Neurobiol. Dis. 2013; 49: 190-198Crossref PubMed Scopus (36) Google Scholar). In the present study, the assessment of LC3 II at basal level and after bafilomycin administration has demonstrated a dysregulation of autophagy in patients. Moreover, a defective activity has been found in some lysosomal enzymes. These data are corroborated by the findings observed in the two twins. These results suggest that a generalized autophagic defect is involved in MSA. Further studies will be crucial to the understanding of whether autophagic deficiency represents a primary defect of the disease or is a consequence of other mechanisms (e.g., protein/lipid accumulation), with a particular focus on the relationship between autophagy and α-synuclein. Mitochondrial dysfunction has been widely investigated in Parkinson’s disease, and many clues strongly suggest an involvement in the pathogenesis (Schapira, 2008Schapira A.H. Mitochondria in the aetiology and pathogenesis of Parkinson's disease.Lancet Neurol. 2008; 7: 97-109Abstract Full Text Full Text PDF PubMed Scopus (617) Google Scholar). Furthermore, as reported in detail in the Introduction, mitochondria have been extensively studied also in MSA. The results of the present study support the hypothesis of mitochondrial involvement in the pathogenesis of the disease. In particular, they suggest mitochondrial dysfunction and an upregulation of several mitochondrial pathways, findings that may be closely related to each other. Indeed, the generalized mitochondrial upregulation may suggest a mitochondrial attempt to compensate the functional deficit. Mitochondrial dysfunction is supported by spectrophotometric analyses, which show an impaired activity of respiratory chain complexes, in particular complex II and complexes II + III. On the other hand, the mitochondrial attempt to counterbalance the functional defect is suggested by the increased mitochondrial mass (assessed through two independent methods), the increased amount of respiratory chain complexes II and III, and the upregulation of several enzymes involved in CoQ10 synthesis. CoQ10 is a component of the mitochondrial respiratory chain that shuttles electrons from complexes I and II to complex III. The involvement of CoQ10 deficiency in the pathogenesis of MSA has been previously suggested (Multiple-System Atrophy Research Collaboration, 2013Multiple-System Atrophy Research CollaborationMutations in COQ2 in familial and sporadic multiple-system atrophy.N. Engl. J. Med. 2013; 369: 233-244Crossref PubMed Scopus (191) Google Scholar, Schottlaender et al., 2016Schottlaender L.V. Bettencourt C. Kiely A.P. Chalasani A. Neergheen V. Holton J.L. Hargreaves I. Houlden H. Coenzyme Q10 levels are decreased in the cerebellum of multiple-system atrophy patients.PLoS One. 2016; 11: e0149557Crossref PubMed Scopus (30) Google Scholar, Barca et al., 2016Barca E. Kleiner G. Tang G. Ziosi M. Tadesse S. Masliah E. Louis E.D. Faust P. Kang U.J. Torres J. et al.Decreased coenzyme Q10 levels in multiple system atrophy cerebellum.J. Neuropathol. Exp. Neurol. 2016; 75: 663-672Crossref PubMed Scopus (28) Google Scholar). Our finding of an upregulation of various CoQ10 synthesis enzymes, in particular those that catalyze the initial reactions of biosynthesis, is consistent with the hypothesis of a compensatory mechanism. In this case the mechanism is effective, as CoQ10 was not found to be decreased in MSA neurons. The result is in line with findings on autoptic samples, which show a CoQ10 reduction only in cerebellum (Schottlaender et al., 2016Schottlaender L.V. Bettencourt C. Kiely A.P. Chalasani A. Neergheen V. Holton J.L. Hargreaves I. Houlden H. Coenzyme Q10 levels are decreased in the cerebellum of multiple-system atrophy patients.PLoS One. 2016; 11: e0149557Crossref PubMed Scopus (30) Google Scholar, Barca et al., 2016Barca E. Kleiner G. Tang G. Ziosi M. Tadesse S. Masliah E. Louis E.D. Faust P. Kang U.J. Torres J. et al.Decreased coenzyme Q10 levels in multiple system atrophy cerebellum.J. Neuropathol. Exp. Neurol. 2016; 75: 663-672Crossref PubMed Scopus (28) Google Scholar). These data may suggest that an efficient compensatory mechanism is active in most brain regions with the exception of cerebellum, which is particularly susceptible to CoQ10-related diseases (Quinzii et al., 2007Quinzii C.M. DiMauro S. Hirano M. Human coenzyme Q10 deficiency.Neurochem. Res. 2007; 32: 723-727Crossref PubMed Scopus (135) Google Scholar). In the attempt to provide a comprehensive hypothesis, we suggest that autophagic and mitochondrial defects may be related. Autophagic impairment may also affect mitophagy, resulting in the accumulation of senescent damaged mitochondria. These organelles do not correctly function, as the impaired complexes' activities show. Consequently, several feedback mechanisms try to overcome this functional deficit by upregulating a series of processes: mitochondrial mass, and synthesis of respiratory chain subunits and of CoQ10. However, dysfunctional mitochondria are not able to successfully carry out these tasks, the result of which is a further accumulation of malfunctioning mitochondria, which contribute to trigger the pathological compensatory mechanism in a self-propagating fashion. This picture prompts us to further investigate the mitophagic machinery in detail in order to confirm the connection between autophagic impairment and mitochondrial defect. Overall, the present study describes a comprehensive model of MSA based on iPSC-derived neurons and suggests innovative perspectives for the comprehension of the pathogenesis of this disease." @default.
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• W2897524551 title "Mitochondrial Dysregulation and Impaired Autophagy in iPSC-Derived Dopaminergic Neurons of Multiple System Atrophy" @default.
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