In neuronal mitophagy, Parkin and OPTN induce efficient sequestration of damaged somal mitochondria into autophagosomes, but slow turnover via lysosomal acidification may be a point of vulnerability for the cell.
Impaired lysosomal acidification results in retention of iron inside lysosomes, triggering functional iron deficiency, dysfunctional mitochondria (especially mtDNA loss), and inflammation in vivo in a mouse model of lysosomal disease.
Cellular and genetic approaches reveal that exposure of a normally buried nuclear export signal (NES)-like sequence mediates export of ALS-linked mutant and misfolded wild-type SOD1 to the cytoplasm by CRM1.
Zfp106 functions as an RNA binding protein, binds directly to GGGGCC RNA repeats, is required in motor neurons to prevent ALS-like neurodegeneration in mice, and can suppress neurotoxicity in an established fly model of ALS.
Protein aggregates resulting from mutations in C9orf72 impair different aspects of cellular quality control in the cytosol and the nucleus, but mRNA-mediated effects contribute more strongly to toxicity.
Prion-like transfer of mutant huntingtin aggregates from presynaptic to postsynaptic neurons is enhanced by neuronal silencing and requires passage through the cytoplasm of Draper-expressing phagocytic glia in adult Drosophila brains.