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Identifier

000434861

Title

Effect of A53T-α-synuclein expression on DRG neurons and on tissues of the peripheral nervous system

Alternative Title

Μελέτη της επίδρασης της έκφρασης της A53T-α-συνουκλεϊνης στους DRG νευρώνες και σε ιστούς του περιφερικού νευρικού συστήματος

Author

Δημουλά, Κωνσταντίνα

Thesis advisor

Ταουφίκ, Ερασμία

Reviewer

Χαραλαμπόπουλος, Ιωάννης
Λογοθέτης, Διομήδης

Abstract

Parkinson's disease (PD) is a common progressive neurodegenerative disorder that affects 1% of the population above 60 years and, among neurological disorders, it is the fastest growing in prevalence, disability and deaths. PD affects predominantly dopamine-producing neurons in the brain area called substantia nigra and disrupts the facilitation of voluntary movements, thus disability in patients with PD is primarily due to impaired motor function. The hallmark of the PD pathology is the aggregation of the protein α-synuclein into Lewy bodies, a pathology that adopts a prion-like spreading pattern. Point mutations in the α-synuclein gene can cause heritable earlyonset PD in rare pedigrees, an example is A53T missense point mutation, which increases the kinetics of α-synuclein fibrillization. Although the mostly considered PD symptoms are motorrelated, up to 85% of PD cases experience pain, even before motor symptoms are prominent, while one third of cases develop sensory neuropathies. PD patients display altered pain thresholds and changes in sensory perception early in the disease progression, which suggests alterations in stimuli processing along the neuronal axis. Studies have also confirmed the correlation between axonal degeneration and α-synuclein deposition. Altered pain thresholds of sensory neurons could imply alterations in excitability at the level of voltage gated sodium channels (NaVs), which are critically important for electrogenesis. The expression of NaV1.8 subtype, that is highly expressed in nociceptors, is said to be altered upon axotomy and inflammation. Currently, this PD-related sensory system dysregulation is insufficiently investigated, thus the present study aims to study aspects of sensory processing in the transgenic A53T mouse model, which expresses the mutated form of human α-synuclein. Characterization of primary dorsal root ganglion (DRG) cultures derived from A53T homozygous mice confirms the deposition of A53T α-synuclein in DRG neurons, while expression of the transgene is correlated with larger DRG’s soma. A53T DRGs exhibit numerous areas of axonal degeneration and they are susceptible to stress, induced by the proteasome’s inhibitor, epoxomicin. Also, calcium transients of A53T DRGs seem to be inefficiently evoked by KCl. NaV1.8 expression is elevated affected by the A53T α-synuclein in DRG neurons, while it is reduced in the sciatic nerve tissue, where loss of axonal material is observed. A53T and wild type mice have a similar pattern of epidermal footpad innervation and no significant differences are observed in terms of behavioral evaluation of coldinduced pain. These findings suggest that the differences in NaV1.8 expression detected in A53T DRG primary cultures and A53T sciatic nerve tissue could be part of the remodelling process following axonopathy. Further electrophysiological and behavioral evaluation of sensory processing in A53T mice would be a desirable research plan in the future.

Language

English

Subject

Parkinson's disease

Πάρκινσον

Περιφερικό νευρικό σύστημα

Issue date

2020-12-17

Collection

School/Department--School of Medicine--Department of Medicine--Post-graduate theses

Type of Work--Post-graduate theses

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