Institutional creator:

Instytut Biologii Doświadczalnej im. Marcelego Nenckiego PAN

Contributor:

Rędowicz, Maria Jolanta : Supervisor ; Gawor, Marta : Supevisor

Publisher:

Nencki Institute of Experimental Biology PAS

Place of publishing:

Warsaw

Description:

183 pages : illustrations ; 30 cm ; Bibliography ; Summary in Polish

Degree grantor:

Instytut Biologii Doświadczalnej im. Marcelego Nenckiego PAN

Type of object:

Thesis

Abstract:

The neuromuscular junction (NMJ) is a chemical synapse of the peripheral nervous system that enables skeletal muscle contraction through acetylcholine-mediated neurotransmission. This synaptic structure is composed of three main elements, motor neuron, myofiber, and Schwann cells, that tightly regulate one another throughout ontogenesis via multiple signaling pathways. Disruption of these pathways can result in neuromuscular disorders that reduce the efficiency of muscle contraction and lead to muscle fatigue, wasting, and, in some cases, premature death. The cause of many neuromuscular disorders remains unknown to this date and any cure or treatment is often missing. Studying the molecular mechanisms underlying NMJ function in physiological and pathological contexts could shed light on these unmet clinical needs and even lay the path to discovering therapeutic targets. Impairments in cellular processes regulating the presence of acetylcholine receptors (AChRs) on the myofiber surface are one of the most devastating for proper NMJ function. Most importantly, many signaling pathways and developmental processes involved in receptor clustering and maintenance remain poorly understood, and researchers continue to unveil new roles for proteins whose relevance at the NMJ had been unknown before. The actin cytoskeleton and actin-remodeling proteins are at the core of many postsynaptic-regulating processes, including local delivery and recycling of synaptic components, stabilization of postsynaptic complexes, and recruitment of other cytoskeletal filaments. Through my PhD research, I identified and characterized for the first time some of the functions of the cytoskeletal regulators drebrin and myosin VI in the formation and maintenance of the postsynaptic machinery. Specifically, I found that drebrin plays an important role in AChR clustering and maturation through its ability to rearrange actin filaments. Moreover, its mechanisms of action at the postsynaptic machinery seem to involve microtubule organization and interaction with rapsyn, a key AChR clustering mediator and stabilizer. Myosin VI, on the other hand, does not seem to be crucial neither for NMJ formation nor maturation, however its absence in mice significantly impairs NMJ structure and leads to reduced muscle strength, particularly in females. Altogether, my results provide an insight into the mechanisms through which drebrin mediates AChR cluster formation, maturation, and maintenance, as well as the functional consequences of myosin VI loss in the skeletal muscle of mice

Detailed Resource Type:

PhD Dissertations

Resource Identifier:

oai:rcin.org.pl:236267

Source:

IBD PAN, call no. 20056

Language:

eng

Language of abstract:

pol

Digitizing institution:

Nencki Institute of Experimental Biology of the Polish Academy of Sciences

Original in:

Library of the Nencki Institute of Experimental Biology PAS

Access:

Open