Similarly, it could be demonstrated in flies that Parkin counteracted SNCA-induced reductions of climbing activity and degenerative cell loss ( 15, 16).
In Drosophila melanogaster fly mutants as invertebrate models of PD, it was observed that PINK1 suppressed SNCA-triggered phenotypes of impaired mobility, cell degeneration and reduced lifespan ( 13, 14). Since most PD patients do not suffer from a monogenic disorder, but rather from polygenic interactions with environmental stressors, it is essential to explore the potential interaction of distinct genetic mechanisms in order to identify converging downstream pathways and putative molecular targets of neuroprotective therapy. Among the autosomal recessive causes of PD, a loss-of-function of the serine–threonine kinase PINK1 or of the ubiquitin-E3-ligase Parkin can lead to juvenile PD ( 9, 10), through hampering cellular stress responses by impaired elimination of dysfunctional mitochondria via fission, trafficking and the autophago-lysosomal pathway ( 11, 12). SNCA is modulated by various post-translational events such as phosphorylation and ubiquitination ( 7), and its accumulation is well established to act as a neurotoxic stressor ( 8). SNCA mutations may lead to particularly early and severe manifestations with complete penetrance ( 5, 6). Whether such a common pathogenesis pathway exists also for PD is a matter of scientific controversy and intense investigation.Īmong the autosomal dominant causes of PD, the increased dosage and missense mutations of alpha-synuclein (SNCA) leading to its gain-of-function and to its accumulation are prominent, because the subsequent aggregation of alpha-synuclein in ‘Lewy bodies’ and ‘Lewy neurites’ is observed not only in the brains of monogenic PD cases but also of most sporadic PD cases. For AD, mutations in amyloid precursor protein, in presenilin-1 and in presenilin-2 were all shown to modulate the beta-amyloid 42/40 ratio as the shared trigger of pathology ( 4). Multiple underlying genetic factors were identified for both entities over the past decades ( 1–3).
The most common neurodegenerative disorders of old age are Alzheimer's disease (AD) with preferential affection of the cerebral cortex, and Parkinson's disease (PD) with preferential affection of the midbrain/brainstem. Thus, our study confirmed that SNCA-triggered neurotoxicity is exacerbated by the absence of PINK1 and identified a novel molecular signature that is detectable early in the course of this double pathology. The observed downregulations for Dapk1, Dcaf17, Rab42 and the novel SNCA-marker Lect1 as well as the upregulations for Dctn5, Mrpl9, Tmem181a, Xaf1 and H2afx reflect changes in ubiquitination, mitochondrial/synaptic/microtubular/cell adhesion dynamics and DNA damage. Global brain transcriptome profiles and qPCR validation experiments identified many consistent transcriptional dysregulations already at the age of 6 weeks, which were absent from SMs. Brain proteome quantifications of ubiquitination sites documented altered degradation of SNCA and the DNA-damage marker H2AX at the age of 18 months. In contrast to SMs, a quarter of DM animals manifested progressive paralysis at ages >1 year and exhibited protein aggregates immunopositive for pSer129-SNCA, p62 and ubiquitin in spinal cord and basal brain. DM animals showed potentiated phenotypes in comparison with both single mutants (SMs), with reduced survival and strongly reduced spontaneous movements from the age of 3 months onwards. We studied their lifespan and behavior, histological and molecular anomalies at late and early ages. Here, we crossed previously characterized mice with A53T-SNCA overexpression and with Pink1 deletion to generate double mutants (DMs). Interactions between these triggers and their convergence onto shared pathways are crucial, but currently conflicting evidence exists. The common age-related neurodegeneration of Parkinson's disease can result from dominant causes like increased dosage of vesicle-associated alpha-synuclein (SNCA) or recessive causes like deficiency of mitophagy factor PINK1.
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