An emerging role for Torsins in Lipid metabolism and NPC biogenesis - The NEP1R1-CTDNEP1/ Lipin pathway regulates PA metabolism for a broad set of cellular events

My project seeks for a further understanding of the neurological movement disorder dystonia in order to provide new therapeutic targets for this incurable type of disease. This neurological disease is the third most common movement disorder and is characterized by abnormal, involuntary muscle contractions that cause twisting movements and force the body into sustained, abnormal postures. Dystonia is a chronical and incurable disease that has a severe impact on daily life of patients. In the last years, very little progress has been made toward new therapies and current available treatments are only focused on alleviating the symptoms.There is thus a high necessity for novel dystonia therapies, yet this requires that we better understand the disease etiology, particularly at the molecular level. Despite this need, dystonia is less studied than other movement disorders of similar prevalence, like Huntington's disease. While most dystonia is sporadic, there are also genetic dystonias. These have overlapping symptoms to sporadic dystonia and are considered as model situations to explore the underlying molecular and cellular mechanisms of dystonia. Many of these genetic dystonias are caused by mutations in genes with poorly defined functions, and thus we still have little understanding of the underlying molecular defects. Recently, my group identified that the protein encoded by the gene responsible for the most common genetic dystonia, TOR1A/DYT1, controls lipid metabolism by suppressing lipin PAP activity. This childhood-onset dystonia affects around 15,000 individuals in Belgium and is caused by a three-base-pair deletion in TOR1A (TOR1A ∆GAG/+) that encodes the endoplasmic reticulum (ER) protein, torsin-1A. There is also a firm link between dystonia and loss of torsin activity as ∆GAG behaves as a loss of function allele in mice and inhibits torsinA binding interactions. Thus, these new data from my group now suggest that lipid targeted therapeutics should be exploited for dystonia. My project now aims at identifying how torsin couples to lipin PAP activity. To study this question, I will define a) a specific model of how torsin affects lipin activity, b) kinases and phosphatases that regulate lipin, c) which lipin phosphorylation state correlates with lipin PAP activity and d) I will identify whether CTDNEPNem1/NEP1R1Spo7 mediates torsin inhibition of lipin. This will not only provide novel information on how animals regulate fat production but may also potentially lead to novel druggable targets. This work has potential impact for dystonia but also other neurological and metabolic diseases like diabetes and obesity.

Publication year:2021

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