Protein Kinases as Therapeutic Targets in Neurodegenerative Diseases

Background: Age-related neurodegenerative disorders, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS), are characterized by progressive neuronal degeneration, synaptic dysfunction, and accumulation of misfolded protein aggregates. These disorders pose serious health risks by causing progressive cognitive impairment, motor dysfunction, disability, and increased mortality among affected individuals. Increasing evidence implicates dysregulated protein kinase signaling in the pathogenesis of these disorders through mechanisms involving aberrant phosphorylation, mitochondrial dysfunction, neuroinflammation, impaired proteostasis, and neuronal death. Consequently, protein kinases have emerged as promising therapeutic targets for disease modification.Methods: This narrative review critically synthesizes current evidence from preclinical and clinical studies investigating protein kinases implicated in major neurodegenerative disorders. Relevant literature focusing on kinase-mediated pathogenic pathways, selective kinase modulation, translational progress, and therapeutic relevance was evaluated and integrated. Key kinases examined include Casein Kinase ۱ delta (CSNK۱D), Colony Stimulating Factor ۱ Receptor (CSF۱R), Dual Leucine Zipper Kinase (DLK), Glycogen Synthase Kinase ۳β (GSK۳B), Leucine Rich Repeat Kinase ۲ (LRRK۲), Mitogen-Activated Protein Kinase ۱۴ (MAPK۱۴), Receptor-Interacting Serine/Threonine-Protein Kinase ۱ (RIPK۱), and Rho-Associated Protein Kinase (ROCK).Results: Evidence from experimental and early clinical investigations demonstrates that selective modulation of dysregulated kinase pathways may attenuate neuroinflammation, reduce pathogenic protein aggregation, preserve neuronal integrity, and improve cellular homeostasis. Several kinase-targeted approaches have shown mechanistic and therapeutic promise across AD, PD, HD, and ALS models. However, despite encouraging translational progress, significant limitations persist, including inadequate blood–brain barrier penetration, off-target toxicity, limited long-term safety data, and insufficient clinical efficacy in advanced-stage trials.Conclusions: Protein kinase signaling represents a mechanistically significant and therapeutically promising target in neurodegenerative disease research. Although kinase-targeted interventions demonstrate substantial potential for disease modification, major challenges related to central nervous system delivery, selectivity, safety, and clinical translation remain unresolved. Further mechanistic investigations and the rational development of highly selective kinase inhibitors are essential to advance effective therapeutic strategies for neurodegenerative disorders.Background: Age-related neurodegenerative disorders, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS), are characterized by progressive neuronal degeneration, synaptic dysfunction, and accumulation of misfolded protein aggregates. These disorders pose serious health risks by causing progressive cognitive impairment, motor dysfunction, disability, and increased mortality among affected individuals. Increasing evidence implicates dysregulated protein kinase signaling in the pathogenesis of these disorders through mechanisms involving aberrant phosphorylation, mitochondrial dysfunction, neuroinflammation, impaired proteostasis, and neuronal death. Consequently, protein kinases have emerged as promising therapeutic targets for disease modification. Methods: This narrative review critically synthesizes current evidence from preclinical and clinical studies investigating protein kinases implicated in major neurodegenerative disorders. Relevant literature focusing on kinase-mediated pathogenic pathways, selective kinase modulation, translational progress, and therapeutic relevance was evaluated and integrated. Key kinases examined include Casein Kinase ۱ delta (CSNK۱D), Colony Stimulating Factor ۱ Receptor (CSF۱R), Dual Leucine Zipper Kinase (DLK), Glycogen Synthase Kinase ۳β (GSK۳B), Leucine Rich Repeat Kinase ۲ (LRRK۲), Mitogen-Activated Protein Kinase ۱۴ (MAPK۱۴), Receptor-Interacting Serine/Threonine-Protein Kinase ۱ (RIPK۱), and Rho-Associated Protein Kinase (ROCK). Results: Evidence from experimental and early clinical investigations demonstrates that selective modulation of dysregulated kinase pathways may attenuate neuroinflammation, reduce pathogenic protein aggregation, preserve neuronal integrity, and improve cellular homeostasis. Several kinase-targeted approaches have shown mechanistic and therapeutic promise across AD, PD, HD, and ALS models. However, despite encouraging translational progress, significant limitations persist, including inadequate blood–brain barrier penetration, off-target toxicity, limited long-term safety data, and insufficient clinical efficacy in advanced-stage trials. Conclusions: Protein kinase signaling represents a mechanistically significant and therapeutically promising target in neurodegenerative disease research. Although kinase-targeted interventions demonstrate substantial potential for disease modification, major challenges related to central nervous system delivery, selectivity, safety, and clinical translation remain unresolved. Further mechanistic investigations and the rational development of highly selective kinase inhibitors are essential to advance effective therapeutic strategies for neurodegenerative disorders.

کلیدواژه ها:

Alzheimer’s disease ، Kinase inhibitors ، Neurodegenerative diseases ، Neuroprotection ، Parkinson’s disease ، Protein kinases ، Therapeutic targets