Abstract
Neurodegenerative diseases are incurable diseases of the nervous system that lead to a progressive loss of brain areas and neuronal subtypes, which is associated with an increase in symptoms that can be linked to the affected brain areas. The key findings that appear in many neurodegenerative diseases are deposits of proteins and the damage of mitochondria, which mainly affect energy production and mitophagy. Several causative gene mutations have been identified in various neurodegenerative diseases; however, a large proportion are considered sporadic. In the last decade, studies linking lipids, and in particular sphingolipids, to neurodegenerative diseases have shown the importance of these sphingolipids in the underlying pathogenesis. Sphingolipids are bioactive lipids consisting of a sphingoid base linked to a fatty acid and a hydrophilic head group. They are involved in various cellular processes, such as cell growth, apoptosis, and autophagy, and are an essential component of the brain. In this review, we will cover key findings that demonstrate the relevance of sphingolipids in neurodegenerative diseases and will focus on neurodegeneration with brain iron accumulation and Parkinson’s disease.
Highlights
An early diagnosis and slowing down disease progression are key in the treatment of Neurodegenerative disorders (ND); there is at least a partial lack of knowledge about the underlying disease pathogenesis, which is a barrier to the development of targeted drugs
While several ND gene mutations have been identified that are causative, the majority of ND remain sporadic, or in the case of Parkinson’s disease (PD), both sporadic and genetic forms of the disease exist. The existence of these genetic forms has enabled the creation of animal models to understand the underlying mechanisms that are affected in ND. Such studies have strongly contributed to our current knowledge and several common molecular mechanisms have been identified to play an important role in the pathogenesis of ND
The most common form of neurodegeneration with brain iron accumulation (NBIA) that occurs in 35–50% of NBIA cases is pantothenate kinase-associated neurodegeneration (PKAN), which arises from mutations in pantothenate kinase 2 (PANK2)
Summary
Neurodegenerative disorders (ND) are progressive disorders that impair specific brain areas or neuronal subtypes, accompanied by a gradual increase in signs and symptoms linked to the affected brain areas. Such studies have strongly contributed to our current knowledge and several common molecular mechanisms have been identified to play an important role in the pathogenesis of ND. One interesting observation is the presence of deposits, including proteins, in, e.g., Alzheimer’s disease (AD) and PD, and iron in PD and neurodegeneration with brain iron accumulation (NBIA) [2,3,4,5,6] It remains, unclear if these deposits are the consequence of upstream cellular defects or rather (partially) the cause of the observed signs. We will discuss the importance of sphingolipids in ND using the findings of two specific NDs, namely NBIA and PD
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