INVESTIGATION OF ALPHA-SYNUCLEIN/TUBULIN INTERACTION IN PRESYNAPTIC MICROTUBULE DYNAMICS IN DOPAMINERGIC NEURONS

The pathological mechanism underlying the degeneration and loss of the dopaminergic (DA) neurons of the substantia nigra pars compacta (SNpc) in Parkinson’s disease (PD) are still unknown. Among them, α-synuclein aggregation, mitochondrial impairment, increase oxidative stress and synaptic dysfunction are often indicated as culprits, although it is unclear whether these events are primary or secondary insults in PD neurodegeneration. Unlike other neurodegenerative diseases where cytoskeletal alterations are linked with mutations in key proteins involved in the progression of the pathology, PD lacks these findings. Nonetheless, microtubule (MT) dysfunction has recently emerged as a putative cause of the selective damage of the striatal DA synapses and consequent reduction in dopamine release that characterize PD clinical symptoms. It was only recently when dynamic MTs were shown to enter the pre- and post-synapse as regulatory elements required for proper neurotransmitter release and synaptic plasticity. In pyramidal neurons, excitatory presynaptic sites are hotspots for MT nucleation, a process that regulates neurotransmission by providing the tracks for targeted bidirectional delivery of a rate-limiting supply of synaptic vesicles (SVs) to sites of stimulated release. Notably, α-synuclein, a small synaptic protein that aggregates in PD becoming the main component of Lewy bodies (LBs) and Lewy neurites (LNs), was recently discovered to promote MT assembly in vitro. α-synuclein-mutated PD forms lose this ability, suggesting a possible new connection between synaptic dysfunction and α-synuclein pathology through a tubulin-mediated mechanism. Here, I investigated whether the α-synuclein/tubulin interaction is a feature of brain synapses and whether α-synuclein is a regulator of MT dynamics in primary DA neurons. I also reported a novel role for α-synuclein in activity-evoked presynaptic MT nucleation at en passant boutons, suggesting that α-synuclein may sustain synaptic transmission also by regulating MT nucleation at sites of release. Overall, these data point to α-synuclein as a novel regulator of MT dynamics in primary neurons and reinforce the idea that MT dysfunction may represent an early insult in the sequence of events leading to DA synapse impairment.

Grantor dc:publisher

Università degli Studi di Milano

Year dc:date

2023

Author dc:creator

• COMINCINI, ALESSANDRO

Contributors dc:contributor

• supervisore: F. Bartolini (Columbia University)
• D. Sulzer (Columbia University) ; scientific tutor: G. Cappelletti
• A. Comincini
• CAPPELLETTI, GRAZIELLA

• α-synuclein
• synaptic microtubule
• Parkinson's disease
• dopaminergic neurons
• Settore BIO/11 - Biologia Molecolare

Statement dc:rights

• info:eu-repo/semantics/openAccess

Language dc:language

eng

Identifier

http://dx.doi.org/10.13130/comincini-alessandro_phd2023-03-30
10.13130/comincini-alessandro_phd2023-03-30

OAI identifier oai:identifier

oai:air.unimi.it:2434/958776