Aging · Nov 24, 2020

A dual inhibitor targeting HMG-CoA reductase and histone deacetylase mitigates neurite degeneration in LRRK2-G2019S parkinsonism

By Lin CH, Lin HY, Fang JM et al.

Parkinson's disease (PD) is among the most common neurodegenerative disorders, and its etiology involves both genetic and environmental factors. The leucine-rich repeat kinase (LRRK2) G2019S mutation is the most common genetic cause of familial and sporadic PD. Current treatment is limited to dopaminergic supplementation, as no disease-modifying therapy is available yet. Recent evidence reveals that HMG-CoA reductase (HMGR) inhibitors (statins) exert neuroprotection through anti-neuroinflammatory effects, and histone deacetylase (HDAC) inhibitors mitigate neurodegeneration by promoting the transcription of neuronal survival factors. We designed and synthesized a dual inhibitor, statin hydroxamate JMF3086, that simultaneously inhibits HMGR and HDAC, and examined its neuroprotective effects on LRRK2-G2019S parkinsonism. JMF3086 restored dopaminergic neuron loss in aged LRRK2-G2019S flies and rescued neurite degeneration in primary hippocampal and dopaminergic neurons isolated from transgenic LRRK2-G2019S mice. The molecular mechanisms included downregulation of ERK1/2 phosphorylation, increased anti-apoptotic Akt phosphorylation, and inhibition of GSK3β activity to maintain cytoskeletal stability in stably transfected LRRK2-G2019S SH-SY5Y human dopaminergic cells. JMF3086 also promoted a-tubulin acetylation and kinesin-1 expression, facilitating antegrade mitochondrial transport in axons. Our findings demonstrate that JMF3086 exerted beneficial effects on restoring LRRK2-G2019S neurite degeneration by maintaining microtubule stability. This dual-target compound may be a promising mechanism-based therapy for PD.

doi.org/10.18632/aging.104165Open accessPubMed 33231564Interventions