Tuesday, April 23, 2024
4/23/2024
Alzheimer’s disease (AD), the most common type of dementia, is characterized by progressive memory loss and impaired cognitive function. The development of these phenotypes associates with extracellular deposition of b- amyloid peptide, accumulation of hyperphosphorylated tau (phospho-tau) protein in brain, and alteration in mitochondrial biology and function. Whether and how mitochondria play role in the formation of b-amyloid plaques, which consist of b-amyloid peptide and neurofibrillary tangles (NFTs) containing phosphor-tau protein, are not clearly understood. Mitochondrial protein homeostasis (mitochondrial proteostasis) is mediated by mitochondrial unfolded protein response (UPRmt). UPRmt is regulated by chaperones such as heat shock protein 60 (HSP60). Oligomerization of HSP60 and association with its cofactor HSP10, maintain mitochondrial proteostasis via folding of naïve proteins and refolding of misfolded proteins. We have generated a unique mouse model by introducing a point mutation at position 3 (D3G) of the mature mitochondrial HSP60 protein (HSP60D3G knock-in mice) via CRISPR-Cas9 approach. HSP60D3G destabilizes the oligomerization of HSP60 leading to the accumulation of unfolded/misfolded proteins in mitochondria. Importantly, a point mutation at position 3 (D3G) of the mature mitochondrial HSP60 protein (HSP60D3G or D29G mutation in HSPD1 gene) also associates with neurodegenerative disorder. Therefore, the utilization of this unique mouse model will address a critical unmet need to characterize the levels and functional significance of b-amyloid and phospho-tau accumulation upon disrupting the mitochondrial proteostasis. Using HSP60D3G knock-in mouse model, we will study molecular insights of AD biology and functional significance of defects in mitochondrial proteostasis. We will dissect the underlying mechanism on whether/how destabilizing mitochondrial proteostasis leads to enhanced levels of b-amyloid and phospho-tau accumulation causing decline of cognitive function in HSP60D3G mouse. We will test our hypothesis that destabilization of mitochondrial proteostasis enhances the accumulation of b-amyloid and phospho-tau in brain causing AD phenotypes in HSP60D3G mice. Two Specific Aims are proposed to test this hypothesis. Aim 1. Determine the significance of defective HSP60 oligomerization on cellular signaling that regulates b- amyloid and phospho-tau in mouse brain. Aim 2. Functional characterization of defective HSP60 oligomerization on cognitive function in HSP60D3G mice. Impact: Androgen deprivation therapy (ADT) associates with increased risk of AD in prostate cancer (PCa) patients. HSP60 is highly upregulated and required for PCa development and progression. Therefore, understanding the impact of defective HSP60 oligomerization will provide deeper understanding on the causes and consequences of developing AD in PCa patients undergoing ADT therapy. The findings may provide the impact of mitochondrial proteostasis in AD biology and prognosis including in PCa patients as well as identify HSP60 as a novel target for the treatment and management of AD in humans.
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