Abstract
Simple SummaryMutations of the ALS2 gene, which encodes for the protein Alsin, are linked to three recessive motor neuron diseases characterized by early onset. Alsin is an intriguing protein characterized by several structured domains with distinct functions. To date, it is not fully understood how the aforementioned domains collaborate in the development of Alsin functions and how mutations, located in specific areas of these domains, correlate with Alsin malfunction and disease onset. This study collects information from the literature rationalized on three levels of investigation: a systemic scale (symptoms of the pathology), a protein scale (molecular phenomena that drive the development of the pathology) and a population scale (comparison between ALS2-related diseases and detected mutations). Differences and similarities among ALS2-related diseases are comprehensively highlighted here and correlated with Alsin mutations.Infantile-onset Ascending Hereditary Spastic Paralysis, Juvenile Primary Lateral Sclerosis and Juvenile Amyotrophic Lateral Sclerosis are all motor neuron diseases related to mutations on the ALS2 gene, encoding for a 1657 amino acids protein named Alsin. This ~185 kDa multi-domain protein is ubiquitously expressed in various human tissues, mostly in the brain and the spinal cord. Several investigations have indicated how mutations within Alsin’s structured domains may be responsible for the alteration of Alsin’s native oligomerization state or Alsin’s propensity to interact with protein partners. In this review paper, we propose a description of differences and similarities characterizing the above-mentioned ALS2-related rare neurodegenerative disorders, pointing attention to the effects of ALS2 mutation from molecule to organ and at the system level. Known cases were collected through a literature review and rationalized to deeply elucidate the neurodegenerative clinical outcomes as consequences of ALS2 mutations.
Highlights
Recessive mutations in the Amyotrophic Lateral Sclerosis type 2 (ALS2) gene are responsible for distinct motor neuron diseases (MNDs) conditions, namely Infantile-onset ascending hereditary spastic paralysis (IAHSP, OMIM:607225), Juvenile Primary Lateral Sclerosis (JPLS, OMIM:606353), and Juvenile Amyotrophic Lateral
IAHSP, JPLS, and Juvenile Amyotrophic Lateral Sclerosis (JALS) are three diseases that can be related to mutations in the ALS2 gene and that share common symptoms, such as spasticity and weakness in the lower limbs, bulbar involvement, anarthria, dysphagia, isolated pyramidal signs, loss of sensation and control of the sphincters, and often loss of motor skills [1,2,3,4,17,19,20,29,30]
Alsin is a protein constituted by three putative guanine exchange factor (GEF) domains [2,4,21]: the RCC1-like domain (RLD) at the N-terminus, the central B cell lymphoma (Dbl) homology (DH) and pleckstrin-homology (PH) domain, and the C-terminal vacuolar protein-sorting 9 (VPS9)
Summary
The lack of knowledge at the molecular level, the limited number of patients, and the lack of research projects involving multidisciplinary networks constrain our ability to obtain a comprehensive view of the disease and how, from specific molecular events, the pathology evolves. Within this vision is placed this review work, which proposes a comparison of IAHSP, JPLS, and JALS, making use of different levels of pathology description. The molecular features of IAHSP, JPLS, and JALS are highlighted, focusing on Alsin and its role in cellular functions, both in physiological and pathological conditions. ALS2-related diseases at different scales, and it attempts to answer to the need for an open-access research framework giving attention to rare neurological conditions such as IAHSP (prevalence < 1:100,000), where scientific advancements are limited by the quantity, availability, heterogeneity, dispersion, and fragmentation of patient data
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