BIOTECHNOLOGY
Figure 2: Representative pathways of mitochondrial dysfunction implicated in the pathophysiology of PD. The listed proteins contribute pathologically to the different pathways. Figure source:
https://doi.org/10.1007/s11910-018-0829-3
neuroinflammation and neuronal death. Conversely, loss-of-function in kinases has emerged as a critical genetic factor and a major contributor to the development of several neurodegenerative diseases. The two main pathological
hallmarks of AD are the extracellular amyloid beta (Aβ) plaques, which result from the accumulation of Aβ, and the intracellular neurofibrillary tangles (NFTs), composed of abnormally phosphorylated tau. Elevated GSK-3β activity is directly linked to tau hyperphosphorylation and increased production, contributing to molecular pathologies, neuronal damage, and cognitive decline in AD. Fyn also represents a compelling therapeutic target for AD, as it is activated by Aβ through the cellular prion protein (PrPC) and also interacts
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with tau, uniquely bridging the two key pathologies in AD. Pathologically, PD is characterised by
the progressive loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) and the accumulation of intracellular α-synuclein in the form of Lewy-body. Mutations in LRRK2 are the most common genetic cause of familial PD and represent a significant risk factor for sporadic PD. Mutations in PTEN- induced kinase 1 (PINK1) are also associated with familial PD. Extensive evidence suggests that mitochondrial dysfunction is a central factor in PD pathophysiology (Figure 2). Mutations in autosomal dominant LRRK2 and autosomal recessive PINK1 are directly linked to mitochondrial dysfunction, highlighting their critical roles in the pathogenesis of PD.
ALS features gradual loss of muscle
controls due to degeneration of motor neurons. MAP4K4, a member of the STE20 family, has been identified as a key regulator of motor neuron degeneration in ALS. Inhibition of MAP4K4 can facilitate neuron survival and prevent neurite degeneration under conditions of exogenous or endogenous stress, suggesting that MAP4K4 is a druggable target for ALS therapeutics.
DEVELOPMENT OF KINASE INHIBITORS FOR THE TREATMENT OF AD, PD, AND ALS In AD: GSK-3β inhibitors have been extensively studied. GSK-3β is involved in tau hyperphosphorylation and Aβ formation, both of which are key pathological features of AD.
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