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• W2912282800 endingPage "130" @default.
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• W2912282800 abstract "Parkinson's disease (PD) is the second most frequent neurodegenerative disorder in the old population. Among its monogenic variants, a frequent cause is a mutation in the Parkin gene (Prkn). Deficient function of Parkin triggers ubiquitous mitochondrial dysfunction and inflammation in the brain, but it remains unclear how selective neural circuits become vulnerable and finally undergo atrophy. We attempted to go beyond previous work, mostly done in peripheral tumor cells, which identified protein targets of Parkin activity, an ubiquitin E3 ligase. Thus, we now used aged Parkin-knockout (KO) mouse brain for a global quantification of ubiquitylated peptides by mass spectrometry (MS). This approach confirmed the most abundant substrate to be VDAC3, a mitochondrial outer membrane porin that modulates calcium flux, while uncovering also >3-fold dysregulations for neuron-specific factors. Ubiquitylation decreases were prominent for Hippocalcin (HPCA), Calmodulin (CALM1/CALML3), Pyruvate Kinase (PKM2), sodium/potassium-transporting ATPases (ATP1A1/2/3/4), the Rab27A-GTPase activating protein alpha (TBC1D10A) and an ubiquitin ligase adapter (DDB1), while strong increases occurred for calcium transporter ATP2C1 and G-protein subunits G(i)/G(o)/G(Tr). Quantitative immunoblots validated elevated abundance for the electrogenic pump ATP1A2, for HPCA as neuron-specific calcium sensor, which stimulates guanylate cyclases and modifies axonal slow afterhyperpolarization (sAHP), and for the calcium-sensing G-protein GNA11. We assessed if compensatory molecular regulations become insufficient over time, leading to functional deficits. Patch clamp experiments in acute Parkin-KO brain slices indeed revealed alterations of the electrophysiological properties in aged noradrenergic locus coeruleus (LC) neurons. LC neurons of aged Parkin-KO brain showed an acceleration of the spontaneous pacemaker frequency, a reduction in sAHP and shortening of action potential duration, without modulation of KCNQ potassium currents. These findings indicate altered calcium-dependent excitability in a PARK2 model of PD, mediated by diminished turnover of potential Parkin targets such as ATP1A2 and HPCA. The data also identified further novel Parkin substrate candidates like SIRT2, OTUD7B and CUL5. Our elucidation of neuron-specific mechanisms of PD pathogenesis helps to explain the known exceptional susceptibility of noradrenergic and dopaminergic projections to alterations of calcium homeostasis and its mitochondrial buffering." @default.
• W2912282800 created "2019-02-21" @default.
• W2912282800 creator A5000222290 @default.
• W2912282800 creator A5001223233 @default.
• W2912282800 creator A5008201869 @default.
• W2912282800 creator A5009167156 @default.
• W2912282800 creator A5009272032 @default.
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• W2912282800 creator A5065099034 @default.
• W2912282800 creator A5074114388 @default.
• W2912282800 creator A5084929882 @default.
• W2912282800 date "2019-07-01" @default.
• W2912282800 modified "2023-10-03" @default.
• W2912282800 title "Ubiquitylome profiling of Parkin-null brain reveals dysregulation of calcium homeostasis factors ATP1A2, Hippocalcin and GNA11, reflected by altered firing of noradrenergic neurons" @default.
• W2912282800 cites W1482509014 @default.
• W2912282800 cites W1522193348 @default.
• W2912282800 cites W1618846043 @default.
• W2912282800 cites W1673848766 @default.
• W2912282800 cites W1895032132 @default.
• W2912282800 cites W1941635000 @default.
• W2912282800 cites W1966932072 @default.
• W2912282800 cites W1970093299 @default.
• W2912282800 cites W1970133497 @default.
• W2912282800 cites W1970429881 @default.
• W2912282800 cites W1973832002 @default.
• W2912282800 cites W1979645469 @default.
• W2912282800 cites W1980587214 @default.
• W2912282800 cites W1984148608 @default.
• W2912282800 cites W1984921184 @default.
• W2912282800 cites W1986118996 @default.
• W2912282800 cites W1986685849 @default.
• W2912282800 cites W1988197452 @default.
• W2912282800 cites W1989293830 @default.
• W2912282800 cites W1989989056 @default.
• W2912282800 cites W1991447709 @default.
• W2912282800 cites W1995700909 @default.
• W2912282800 cites W2000194968 @default.
• W2912282800 cites W2003961668 @default.
• W2912282800 cites W2010769330 @default.
• W2912282800 cites W2011894009 @default.
• W2912282800 cites W2012016703 @default.
• W2912282800 cites W2012393013 @default.
• W2912282800 cites W2012968975 @default.
• W2912282800 cites W2013828402 @default.
• W2912282800 cites W2015001023 @default.
• W2912282800 cites W2018241116 @default.
• W2912282800 cites W2018877910 @default.
• W2912282800 cites W2021272772 @default.
• W2912282800 cites W2022124171 @default.
• W2912282800 cites W2023168684 @default.
• W2912282800 cites W2024696684 @default.
• W2912282800 cites W2025518994 @default.
• W2912282800 cites W2028592029 @default.
• W2912282800 cites W2029305459 @default.
• W2912282800 cites W2031263781 @default.
• W2912282800 cites W2034087770 @default.
• W2912282800 cites W2034243446 @default.
• W2912282800 cites W2035526886 @default.
• W2912282800 cites W2038067616 @default.
• W2912282800 cites W2040462263 @default.
• W2912282800 cites W2043684970 @default.
• W2912282800 cites W2043806914 @default.
• W2912282800 cites W2044687129 @default.
• W2912282800 cites W2048528277 @default.
• W2912282800 cites W2049161582 @default.
• W2912282800 cites W2051283777 @default.
• W2912282800 cites W2052874989 @default.
• W2912282800 cites W2053071718 @default.
• W2912282800 cites W2058262968 @default.
• W2912282800 cites W2060420349 @default.
• W2912282800 cites W2061330513 @default.
• W2912282800 cites W2065060908 @default.
• W2912282800 cites W2067518961 @default.
• W2912282800 cites W2070680714 @default.
• W2912282800 cites W2071299561 @default.
• W2912282800 cites W2071453130 @default.
• W2912282800 cites W2072154257 @default.
• W2912282800 cites W2075718968 @default.
• W2912282800 cites W2080443900 @default.
• W2912282800 cites W2083273040 @default.
• W2912282800 cites W2083903439 @default.
• W2912282800 cites W2088990148 @default.
• W2912282800 cites W2089083990 @default.
• W2912282800 cites W2089804882 @default.
• W2912282800 cites W2093420337 @default.
• W2912282800 cites W2095147897 @default.
• W2912282800 cites W2097565031 @default.
• W2912282800 cites W2097704104 @default.
• W2912282800 cites W2097777783 @default.
• W2912282800 cites W2102313940 @default.
• W2912282800 cites W2103156942 @default.
• W2912282800 cites W2105630216 @default.
• W2912282800 cites W2107277218 @default.
• W2912282800 cites W2108900121 @default.
• W2912282800 cites W2110998515 @default.
• W2912282800 cites W2117859867 @default.
• W2912282800 cites W2122440289 @default.
• W2912282800 cites W2128814375 @default.

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