Abstract
As the second most frequent neurodegenerative disorder of the aging population, Parkinson’s disease (PD) is characterized by progressive deficits in spontaneous movement, atrophy of dopaminergic midbrain neurons and aggregation of the protein alpha-synuclein (SNCA). To elucidate molecular events before irreversible cell death, we studied synucleinopathy-induced expression changes in mouse brain and identified 49 midbrain/brainstem-specific transcriptional dysregulations. In particular complexin-1 (Cplx1), Rabl2a and 14-3-3epsilon (Ywhae) downregulation, as well as upregulation of the midbrain-specific factor forkhead box P1 (Foxp1) and of Rabgef1, were interesting as early mRNA level effects of alpha-synuclein triggered pathology. The protein levels of complexin-1 were elevated in midbrain/brainstem tissue of mice with A53T-SNCA overexpression and of mice with SNCA-knockout. The response of CPLX1 and Foxp1 levels to SNCA deficiency supports the notion that these factors are regulated by altered physiological function of alpha-synuclein. Thus, their analysis might be useful in PD stages before the advent of Lewy pathology. Because both alpha-synuclein and complexin-1 modulate vesicle release, our findings support presynaptic dysfunction as an early event in PD pathology.
Highlights
Parkinson’s disease (PD) is the second most frequent ageassociated brain degeneration disorder, affecting about 1 %of the population over 65 years of age
Among the progressive upregulation effects, the increase of forkhead box P1 (Foxp1) mRNA levels by A53T-alpha-synuclein overexpression was interesting in view of our previous finding that Foxp1 is downregulated in alpha-synuclein knockout mouse [15]
Foxp1 appears to depend in its brain levels both on the gainof-function and the loss-of-function of alpha-synuclein
Summary
Parkinson’s disease (PD) is the second most frequent ageassociated brain degeneration disorder, affecting about 1 %of the population over 65 years of age. Surviving neurons in vulnerable regions exhibit aggregates predominantly consisting of the protein alpha-synuclein, which are visualized as Lewy neurites and. Lewy bodies, both in sporadic late-onset and most familial early onset PD variants [2]. Autosomal dominant PD with early clinical manifestation was observed in rare families, leading to the identification of alpha-synuclein (SNCA) protein missense mutations such as. Further recruitment of Parkinson’s families enabled identification of a list of disease genes responsible for monogenic PD [5]. Recent characterization of very large collectives of late-manifesting sporadic PD cases through genomewide allele association studies (GWAS) identified two regions on chromosome 4 (SNCA and GAK/CPLX1 loci) that contain genetic variants predisposing to multifactorial PD [6]. Variations in the SNCA gene 3′-untranslated region (3′-UTR) and its promoter correlated strongly with PD risk [7]
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