MYOSIN-V-BASED HUMAN INHERITED DISEASES: MOLECULAR BASIS OF MYOSIN V RECOGNITION OF INTRACELLULAR CARGO

Mutations in the MYO5A, RAB27A or MLPH genes cause Griscelli syndrome type 1 (GS1), type II (GS2) and type III (GS3), respectively. These syndromes are characterised by skin and hair hypopigmentation associated with oculocutaneous albinism and in the case of GS1 also by neurological impairment. The hypopigmentation defects typical of GS syndromes arises from defects in the formation of a complex between MyoVa and the melanosome-bound Rab27 and melanophilin proteins. The formation of this complex is required for the capturing of melanosomes at the tip of melanocyte dendrites and thus for their transfer to keratinocytes. Less clear is how the neurological manifestations associated with MyoVa dysfunction arise. Recent findings show that MyoV motors, in addition to being required for pigmented organelle transport and lytic cytotoxic granule exocytocis, are required for the short-range transport of secretory granules carrying neurotransmitters and mRNA at synapses and nerve terminals. MyoV mutations causing a primary neurologic deficit cluster within the C-terminal domain of Myosin V. The intracellular transport step affected by these mutations in neurons is unknown. Furthermore, MyoVa loss-of-function has been implicated in neurodegenerative processes. This proposal aims to clarify which and how many pathways involve MyoV and to clarify how MyoVa mutations leading to neurological dysfunction affect these pathways. Moreover, by using genome-wide approaches we aim to identify factors able to bypass MyoVa dysfunctions that lead to neurological alteration.