C9orf72: At the intersection of lysosome cell biology and neurodegenerative disease.

摘要: The discovery that expansion of a hexanucleotide repeat within noncoding region the C9orf72 gene causes amyotrophic lateral sclerosis and frontotemporal dementia raised questions about protein function potential disease relevance. major predicted structural feature is DENN (differentially expressed in normal neoplastic cells) domain. As domains are best characterized for regulation specific Rab GTPases, it has been proposed may also act through GTPase target. Recent genetic cell biological studies furthermore indicate functions at lysosomes as part larger complex contains Smith-Magenis chromosome 8 (SMCR8) WD repeat-containing 41 (WDR41) proteins. An important role supported by defects lysosome morphology mTOR 1 (mTORC1) signaling arising from KO diverse model systems. Collectively, these new findings define C9orf72-containing lysosomal site action central to provide foundation elucidation direct physiological targets C9orf72. Further mechanisms whereby regulates will help determine how reductions expression levels accompany expansions contribute pathology.