Gibbs, W. S. | bioRxiv Science

bioRxiv2024

Loss of SARM1 protects against retinal ganglion cell degeneration in Autosomal Dominant Optic Atrophy

Autosomal Dominant Optic Atrophy (ADOA), the most prevalent inherited optic neuropathy, leads to retinal ganglion cell (RGC) degeneration and vision loss. ADOA is primarily caused by mutations in the OPA1 gene, which encodes a conserved GTPase important for mitochondrial inner membrane dynamics. To date, the disease mechanism remains unclear, and no therapies are available. Here, we present a novel mouse model carrying the pathogenic Opa1R290Q/+ allele that recapitulates key features of human ADOA, including mitochondrial defects, age-related RGC loss, optic nerve degeneration, and reduced RGC functions. We identify SARM1, a neurodegeneration switch, as a key driver of RGC degeneration in these mice. Sarm1 knockout nearly completely suppresses all the degeneration phenotypes. Additionally, we show that SARM1 is located within the mitochondrial intermembrane space (IMS). These findings indicate that SARM1 is activated downstream of mitochondrial dysfunction in ADOA, highlighting it as a promising therapeutic target.

neuroscience↗

bioRxiv2023

The LRRK2 kinase substrates Rab8a and Rab10 contribute complementary but distinct disease-relevant phenotypes in human neurons

Mutations in the LRRK2 gene cause familial Parkinsons disease presenting with pleomorphic neuropathology that can involve -synuclein or tau accumulation. LRRK2 mutations are thought to converge toward a pathogenic increase in LRRK2 kinase activity. A subset of small Rab GTPases have been identified as LRRK2 substrates, with LRRK2-dependent phosphorylation resulting in Rab inactivation. We used CRISPR/Cas9 genome editing to generate a novel series of isogenic iPSC lines deficient in the two most well validated LRRK2 substrates, Rab8a and Rab10, from two independent, deeply phenotyped healthy control lines. Thorough characterization of NGN2-induced neurons revealed divergent effects of Rab8a and Rab10 deficiency on lysosomal pH, LAMP1 association with Golgi, -synuclein insolubility and tau phosphorylation, while parallel effects on lysosomal numbers and Golgi clustering were observed. Our data demonstrate largely antagonistic effects of genetic Rab8a or Rab10 inactivation which provide discrete insight into the pathologic features of their biochemical inactivation by pathogenic LRRK2 mutation. HighlightsO_LIRab8a and Rab10 deficiency induce lysosomal and Golgi defects C_LIO_LIRab8a and Rab10 deficiency induce opposing effects on lysosomal pH C_LIO_LIRab8a KO and Rab10 KO neurons show divergent effects on synuclein and tau proteostasis C_LIO_LIInactivation of different Rab GTPases can induce distinct disease-relevant phenotypes C_LI

neuroscience↗