Parkin and PINK1 play an important role in mitochondrial quality control, whose malfunction may also be involved in the pathogenesis of amyotrophic lateral sclerosis (ALS).
Moreover, both overexpression of Miro1 and ablation of PINK1 rescued the mitochondrial axonal transport deficit in ALS mutant SOD1-expressing cortical and motor neurons.
In our genetic screening, Pink1 and Park genes were identified as modifiers of neurodegeneration phenotypes induced by wild type (Wt) or ALS-associated P525L-mutant human FUS.
The impact of PINK1-mediated phosphorylation of Ub and TBK1-dependent phosphorylation of autophagy receptors (OPTN and p62) has been recently linked to the development of Parkinson's disease and amyotrophic lateral sclerosis, respectively.
Together with the significant decrease of PINK1 mRNA levels in human ALS muscle tissue, statistically nonsignificant reduction of DJ-1 mRNA levels, and reduced immunostaining for PINK1 in human ALS muscle, the results suggest potential pathophysiologic roles for these proteins in both mutant SOD1 transgenic mice and in sporadic ALS(G93A).
Direct sequencing analyses were performed in 19 genes, including ALS/frontotemporal lobar degeneration (FTLD)-related genes (SOD2, SOD3, ALS2/alsin, SMN1, PGRN, ANG, VEGF, VCP, VAPB, DCTN1, CHMP2B, and TARDBP or TDP-43), tauopathy-related gene (GSK3beta), and parkinsonism-related genes (alpha-synuclein, LRRK2, parkin, DJ-1, PINK1, and ATP13A2).