Abstract
Hereditary Parkinson’s disease (PD) can be triggered by an autosomal dominant overdose of alpha-Synuclein (SNCA) as stressor or the autosomal recessive deficiency of PINK1 Serine/Threonine-phosphorylation activity as stress-response. We demonstrated the combination of PINK1-knockout with overexpression of SNCAA53T in double mutant (DM) mice to exacerbate locomotor deficits and to reduce lifespan. To survey posttranslational modifications of proteins underlying the pathology, brain hemispheres of old DM mice underwent quantitative label-free global proteomic mass spectrometry, focused on Ser/Thr-phosphorylations. As an exceptionally strong effect, we detected >300-fold reductions of phosphoThr1928 in MAP1B, a microtubule-associated protein, and a similar reduction of phosphoSer3781 in ANK2, an interactor of microtubules. MAP1B depletion is known to trigger perturbations of microtubular mitochondria trafficking, neurite extension, and synaptic function, so it was noteworthy that relevantly decreased phosphorylation was also detected for other microtubule and microfilament factors, namely MAP2S1801, MARK1S394, MAP1AT1794, KIF1AS1537, 4.1NS541, 4.1GS86, and ADD2S528. While the MAP1B heavy chain supports regeneration and growth cones, its light chain assists DAPK1-mediated autophagy. Interestingly, relevant phosphorylation decreases of DAPK2S299, VPS13DS2429, and VPS13CS2480 in the DM brain affected regulators of autophagy, which are implicated in PD. Overall, significant downregulations were enriched for PFAM C2 domains, other kinases, and synaptic transmission factors upon automated bioinformatics, while upregulations were not enriched for selective motifs or pathways. Validation experiments confirmed the change of LC3 processing as reflection of excessive autophagy in DM brain, and dependence of ANK2/MAP1B expression on PINK1 levels. Our new data provide independent confirmation in a mouse model with combined PARK1/PARK4/PARK6 pathology that MAP1B/ANK2 phosphorylation events are implicated in Parkinsonian neurodegeneration. These findings expand on previous observations in Drosophila melanogaster that the MAP1B ortholog futsch in the presynapse is a primary target of the PARK8 protein LRRK2, and on a report that MAP1B is a component of the pathological Lewy body aggregates in PD patient brains. Similarly, ANK2 gene locus variants are associated with the risk of PD, ANK2 interacts with PINK1/Parkin-target proteins such as MIRO1 or ATP1A2, and ANK2-derived peptides are potent inhibitors of autophagy.
Highlights
Parkinson’s disease (PD) is the second most frequent neurodegenerative disorder
double mutant (DM) mouse brains with A53T-SNCA overexpression as stressor and with PINK1 deletion to impair stress-responses were employed in a pioneer Ser/Thr-phosphorylome survey by quantitative label-free mass spectrometry
Validation experiments provided additional evidence that MAP1B is modulated by PINK1 and that reduced autophagosome availability exists in DM neurons
Summary
Parkinson’s disease (PD) is the second most frequent neurodegenerative disorder. its most important risk factor is old age, there are genetic variants that exacerbate the risk [1].In patients without familial inheritance, genome-wide surveys have implicated dozens of genes in the pathogenesis, with the biggest impact being due to single nucleotide polymorphisms within the alpha-synuclein gene (gene symbol SNCA). Any sporadic PD patient with typical manifestation after the age of 70 years carries a certain mutation burden. The A53T mutation in alpha-synuclein was first identified and is responsible for the PARK1 variant of PD, with onset age around 50 years and autosomal dominant inheritance. Gene triplication and duplication of the alpha-synuclein gene without missense-mutation causes PD via gene dosage effects, with clinical onset after 30 years and 50 years, respectively. Autosomal dominant pedigrees led to the identification of the LRRK2 gene as the most frequent cause of genetic PD (PARK8), but the manifestation age is usually later and the penetrance is limited, so it is harder to explore its mutation effects in disease models
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