Neurodegenerative diseases involve a gradual decline in motor and/or cognitive functions due to the specific loss of neurons in the central nervous system (CNS). Mounting evidence suggests that early pathological events, such as synapse damage and axonal degeneration, precede neuronal cell death and the clinical onset of these diseases. In Parkinson's disease (PD), the loss of dopaminergic fibers in the striatum precedes the degeneration of dopaminergic cell bodies. Mutations in the LRRK2 gene are the primary cause of familial PD, and variations around the LRRK2 locus increase the overall lifetime risk of PD. LRRK2 is a multifunctional serine-threonine kinase highly expressed in the striatum, proposed to play a crucial role at the synapse. In medium spiny neurons (MSNs) within the striatum, the neurotrophin BDNF regulates the remodeling of dendritic spines and synaptic dynamics by binding to its receptor TrkB. Importantly, BDNF levels are diminished in cases of sporadic PD, and specific BDNF variants heighten the risk of LRRK2-associated PD. Building upon preliminary data indicating an elevation in LRRK2 phosphorylation at Ser935 following BDNF stimulation, this project explores the molecular mechanisms of LRRK2-mediated BDNF/TrkB signaling. This investigation presents evidence supporting the involvement of LRRK2 downstream of BDNF cascades, hinting at its potential role in regulating the trafficking of the BDNF receptor TrkB.
Le malattie neurodegenerative comportano un progressivo deterioramento delle funzioni motorie e/o cognitive a causa della perdita selettiva di neuroni nel sistema nervoso centrale (SNC). Un crescente corpus di evidenze suggerisce che eventi patologici iniziali, come danni sinaptici e degenerazione assonale, precedano la morte neuronale e l'esordio clinico di tali patologie. Nel morbo di Parkinson (PD), la perdita di fibre dopaminergiche nello striato si verifica prima della degenerazione dei corpi cellulari dopaminergici. Le mutazioni nel gene LRRK2 rappresentano la causa più comune del PD familiare, mentre variazioni intorno al locus LRRK2 aumentano il rischio di PD nell'arco della vita. LRRK2 è una chinasi serina-treonina multidominio altamente espressa nello striato, e si ipotizza che svolga un ruolo chiave alla sinapsi. Nei neuroni spino-mediali (MSNs) nello striato, il BDNF coordina la strutturazione delle spine dendritiche e la dinamica sinaptica legandosi al suo recettore TrkB. Importante sottolineare che i livelli di BDNF sono ridotti nei casi sporadici di PD, e alcune varianti di BDNF aumentano il rischio di PD associato a LRRK2. Questa ricerca fornisce prove a favore dell'implicazione di LRRK2 in seguito alle cascate di BDNF, suggerendo il suo possibile ruolo nella regolazione del traffico del recettore TrkB.
Role of BDNF in cellular models of LRRK2-linked Parkinson disease
MOROSIN, ESTER
2023/2024
Abstract
Neurodegenerative diseases involve a gradual decline in motor and/or cognitive functions due to the specific loss of neurons in the central nervous system (CNS). Mounting evidence suggests that early pathological events, such as synapse damage and axonal degeneration, precede neuronal cell death and the clinical onset of these diseases. In Parkinson's disease (PD), the loss of dopaminergic fibers in the striatum precedes the degeneration of dopaminergic cell bodies. Mutations in the LRRK2 gene are the primary cause of familial PD, and variations around the LRRK2 locus increase the overall lifetime risk of PD. LRRK2 is a multifunctional serine-threonine kinase highly expressed in the striatum, proposed to play a crucial role at the synapse. In medium spiny neurons (MSNs) within the striatum, the neurotrophin BDNF regulates the remodeling of dendritic spines and synaptic dynamics by binding to its receptor TrkB. Importantly, BDNF levels are diminished in cases of sporadic PD, and specific BDNF variants heighten the risk of LRRK2-associated PD. Building upon preliminary data indicating an elevation in LRRK2 phosphorylation at Ser935 following BDNF stimulation, this project explores the molecular mechanisms of LRRK2-mediated BDNF/TrkB signaling. This investigation presents evidence supporting the involvement of LRRK2 downstream of BDNF cascades, hinting at its potential role in regulating the trafficking of the BDNF receptor TrkB.File | Dimensione | Formato | |
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https://hdl.handle.net/20.500.12608/67168