Pathological microtubule dynamics in Parkinson’s disease: Mechanisms and therapeutic implications

Mar 28, 2026Advances in protein chemistry and structural biology

Abnormal cell structure changes in Parkinson's disease: Causes and possible treatments

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Abstract

Parkinson's disease (PD) is associated with the degeneration of dopaminergic neurons and the accumulation of misfolded α-synuclein.

Microtubule dysregulation may contribute to the pathogenesis of PD by affecting cytoskeletal integrity and neuronal survival.
Mutations linked to PD, such as those in SNCA, Parkin, PINK1, and LRRK2, are associated with microtubule destabilization and impaired axonal transport.
A cycle of microtubule disruption and α-synuclein aggregation could lead to synaptic failure and loss of dopaminergic neurons.
Emerging therapeutic strategies targeting microtubule stabilization may include LRRK2 inhibitors and agents like Epothilone D.
Challenges such as the blood-brain barrier and variability in patient responses to treatments are critical considerations for future research.

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Parkinson's disease (PD) is a progressive neurodegenerative disorder primarily marked by the degeneration of dopaminergic neurons in the substantia nigra and the pathological accumulation of misfolded α-synuclein in Lewy bodies. This chapter explores the underrecognized role of microtubule (MT) dysregulation in PD pathogenesis, linking disruptions in cytoskeletal integrity to impaired axonal transport and neuronal survival. The fundamental biology of MTs, their dynamics, and their regulation by motor proteins and associated proteins like MT-associated proteins (MAPs), tau, and gamma-tubulin complexes. Special attention is given to how mutations linked to PD, such as those in SNCA (α-synuclein), Parkin, PINK1 (PTEN-induced kinase 1), and LRRK2 (leucine-rich repeat kinase 2), lead to MT destabilization, impaired mitophagy, and disruptions in axonal transport. A self-perpetuating cycle of MT disruption and α-synuclein aggregation is proposed, resulting in synaptic failure and dopaminergic neuron loss. The chapter also evaluates emerging therapeutic strategies targeting MT stabilization, including LRRK2 inhibitors, MT-stabilizing agents like Epothilone D, and approaches to modulate α-synuclein aggregation. Challenges such as the blood-brain barrier, off-target effects of MT-targeting drugs, and patient-specific variability in drug response are critically discussed. The future directions include CRISPR-Cas9-based gene therapies and personalized medicine, emphasizing the need for a deeper understanding of PD-related molecular pathways. This comprehensive overview highlights MT dynamics not just as collateral damage but as a central element in PD pathology, offering novel insights into potential avenues for intervention.

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Pathological microtubule dynamics in Parkinson’s disease: Mechanisms and therapeutic implications

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