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Review
. 2022 Jan 5;11(1):77.
doi: 10.3390/biology11010077.

ALS2-Related Motor Neuron Diseases: From Symptoms to Molecules

Marcello Miceli  1 , Cécile Exertier  2 , Marco Cavaglià  1 , Elena Gugole  2 , Marta Boccardo  1 , Rossana Rita Casaluci  1 , Noemi Ceccarelli  1 , Alessandra De Maio  1 , Beatrice Vallone  2 , Marco A Deriu  1
Affiliations
Review

ALS2-Related Motor Neuron Diseases: From Symptoms to Molecules

Marcello Miceli et al. Biology (Basel). .

Abstract

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.

Keywords: Alsin; IAHSP; JALS; JPLS; mutations; neurodegenerative; protein; rare diseases.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic representation of the long and short forms of human Alsin. According to homology modelling, four structured domains, numbered according to the Uniprot Q96Q42 entry, were predicted in human Alsin, namely the RLD (RCC1-like domain), DH-PH (Dbl homology-pleckstrin homology), MORN (membrane occupation and recognition nexus), and VPS9 (vacuolar protein-sorting 9) domains. We used representative structures of these domains (PDB entries 1A12, 2Z0Q, 6T4D, and 2OT3) to illustrate the 3D folds that the RLD, DH-PH, MORN, and VPS9 domains predicted in human Alsin, respectively, may adopt. Structured domains are shown as ribbons with the same color code as the one utilized for the sequence schematic representation.
Figure 2
Figure 2
Reported Alsin mutations, inducing IAHSP, JPLS, and JALS. Mutation positions are indicated with colored stars and type of mutation is reported following a commonly used nomenclature (e.g., G49R).
See this image and copyright information in PMC

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