PAK1 in Alzheimer’s and Huntington’s Diseases

摘要: Among a variety of neurodegenerative diseases, Alzheimer’s disease (AD) and Huntington’s (HD) have been particularly well studied at the genetic molecular levels. The progressive cognitive decline in AD patients is known to be most closely associated with pathological signature amyloid-β (Aβ) protein deposited extracellular plaques intraneuronal neurofibrillary tangles (NFT) consisting largely tau protein. heterogeneous can caused either by rare autosomal dominant mutations elevating aggregation-prone Aβ or mix environmental risk factors. In contrast, sole cause HD huntingtin gene that lead oligomerization its product (huntingtin) extra oligoGln (also called polyQ) resulting neurotoxicity. Loss synapses dendritic spines vulnerable areas are early indices related deficits various including HD. aggregates activate GTPases, RAC CDC42 via Tiam 1 Ca 2+- dependent manner, these GTPases turn kinase PAK1, which directly activates LIM (LIMK). LIMK inactivates cofilin F-actin severing protein, eventually stimulates actin polymerization, disrupting dynamics, formation rods disruption spines. Imbalances dynamics also occur other cell types, such as through influencing actomyosin-dependent phagocytosis neurons microglia. SRC family Tyr inhibitor PP2, curcumin, block PAK1 activation oligomer-treated neurons. Similarly, models, enhances polyQ We discuss potential viable target for therapy both