Lipid Dyshomeostasis and Inherited Cerebellar Ataxia

Abstract

Cerebellar ataxia is a form of ataxia that originates from dysfunction of the cerebellum, but may involve additional neurological tissues. Its clinical symptoms are mainly characterized by the absence of voluntary muscle coordination and loss of control of movement with varying manifestations due to differences in severity, in the site of cerebellar damage and in the involvement of extracerebellar tissues. Cerebellar ataxia may be sporadic, acquired, and hereditary. Hereditary ataxia accounts for the majority of cases. Hereditary ataxia has been tentatively divided into several subtypes by scientists in the field, and nearly all of them remain incurable. This is mainly because the detailed mechanisms of these cerebellar disorders are incompletely understood. To precisely diagnose and treat these diseases, studies on their molecular mechanisms have been conducted extensively in the past. Accumulating evidence has demonstrated that some common pathogenic mechanisms exist within each subtype of inherited ataxia. However, no reports have indicated whether there is a common mechanism among the different subtypes of inherited cerebellar ataxia. In this review, we summarize the available references and databases on neurological disorders characterized by cerebellar ataxia and show that a subset of genes involved in lipid homeostasis form a new group that may cause ataxic disorders through a common mechanism. This common signaling pathway can provide a valuable reference for future diagnosis and treatment of ataxic disorders.

ACSL4-Mediated Ferroptosis and Its Potential Role in Central Nervous System Diseases and Injuries

“…Among the peroxidases, ACSL4 is mainly involved in β-oxidation and the synthesis of alkyl lipids. In the endoplasmic reticulum (ER), it promotes glycerolipid synthesis and ω-oxidation, serving as the primary pathway for catabolism of medium-chain fatty acids when β-oxidation is impaired [ 14 , 15 ]. The aforementioned findings highlight the critical involvement of ACSL4 in fatty acid metabolism, and it is the only subunit of the ACSLs family that plays an essential and direct role in the process of ferroptosis.…”

Tripeptidyl peptidase II coordinates the homeostasis of calcium and lipids in the central nervous system and its depletion causes presenile dementia in female mice through calcium/lipid dyshomeostasis-induced autophagic degradation of CYP19A1

“…It is believed that IRE1 and PERK sense generalised LBS at the ER, while ATF6 is activated by an increase of specific sphingolipids 23 . In addition, ER-associated protein degradation (ERAD) is essential for maintaining lipid homeostasis 24 , 25 , and it regulates the metabolism of many enzymes involved in lipid synthesis, degradation, and secretion 26 , 27 . In particular, disrupted PC synthesis causes both LBS-induced UPR and ERAD-associated LD dyshomeostasis 20 , 28 .…”