Roles of Mitochondrial CHCHD2 and GPCR-Associated β-arrestin2 in the Pathogenesis of Lewy Body Disorders

Graduation Year

2024

Document Type

Dissertation

Degree

Ph.D.

Degree Name

Doctor of Philosophy (Ph.D.)

Degree Granting Department

Medical Sciences

Major Professor

JungA Alexa Woo, Ph.D.

Committee Member

Krishna M. Bhat, M.D., Ph.D.

Committee Member

Vladimir Uversky, Ph.D., D.Sc.

Committee Member

Lianchun Wang, M.D.

Keywords

CHCHD10, lysosomal dysfunction, neurodegeneration, Parkinson's disease

Abstract

Coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2) is a mitochondrial protein that plays important roles in cristae structure, oxidative phosphorylation, and apoptosis. Multiple mutations in CHCHD2 have been associated with Lewy body disorders (LBDs), such as Parkinson’s disease (PD) and dementia with Lewy bodies (DLB), with the CHCHD2T61I mutation being the most widely studied. We generated the first transgenic mouse models expressing human CHCHD2WT and the PD-linked CHCHD2T61I mutation driven by the mPrP promoter. CHCHD2T61I Tg, but not CHCHD2WT Tg mice exhibit perinuclear mitochondrial aggregates, neuroinflammation, and have impaired long-term synaptic plasticity associated with synaptic dysfunction. Dopaminergic neurodegeneration, a hallmark of PD, is also observed along with α-synuclein pathology. Unbiased proteomics analysis reveals surprising increases in many insoluble proteins predominantly originating from mitochondria and perturbing multiple canonical biological pathways as assessed by Ingenuity Pathway Analysis, including neurodegenerative disease-associated proteins such as tau, cofilin, SOD1, and DJ-1. CHCHD2T61I Tg mice exhibit pathological and motor changes associated with LBDs, indicating that this model successfully captures phenotypes seen in human LBD patients with CHCHD2 mutations. We also identify lysosomal cathepsins B and L as preferential interactors of CHCHD2T61I, leading to reduced protease activity in vivo. Acute overexpression of insoluble CHCHD2T61I decreases soluble levels of cysteine cathepsins B and L, with no effect on aspartyl cathepsin D, and increases lysosomal permeabilization. Recombinant CHCHD2T61I aggregates are more difficult to clear than CHCHD2WT, and overexpression of CHCHD2T61I significantly impairs the clearance of pathological [U+F061]Syn PFFs in vitro. Aged CHCHD2T61I Tg mice exhibit increased silver-positive degenerating axons and cognitive dysfunction, further implicating CHCHD2T61I in the pathogenesis of LBDs. These results indicate that CHCHD2T61I promotes multiple proteinopathy via lysosomal dysfunction.Arrestins are multifunctional proteins that regulate G-protein-coupled receptor (GPCR) desensitization, signaling, and internalization. The arrestin family consists of four subtypes: visual arrestin1, β-arrestin1, β-arrestin2, and visual arrestin-4. Recent studies have revealed the multifunctional roles of β-arrestins beyond GPCR signaling, including scaffolding and adapter functions, and physically interacting with non-GPCR receptors. Increasing evidence suggests that β-arrestins are involved in the pathogenesis of a variety of neurodegenerative diseases, including Alzheimer’s disease (AD), frontotemporal dementia (FTD), and Parkinson’s disease (PD). β-arrestins physically interact with γ-secretase, leading to increased production and accumulation of amyloid-beta in AD. Furthermore, β-arrestin oligomers inhibit the autophagy cargo receptor p62/SQSTM1, resulting in tau accumulation and aggregation in FTD. In PD, β-arrestins are upregulated in postmortem brain tissue and an MPTP model, and the β2AR regulates SNCA gene expression. This dissertation provides an overview of β-arrestin1 and β-arrestin2 and describes their physiological functions and roles in neurodegenerative diseases. The multifaceted roles of β-arrestins and their involvement in neurodegenerative diseases suggest that they may serve as promising therapeutic targets.

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