TY  - JOUR
AU  - Mueller, Sarah
AU  - Decker, Lorena
AU  - Menge, Sonja
AU  - Ludolph, Albert C
AU  - Freischmidt, Axel-Dieter
TI  - The Fragile X Protein Family in Amyotrophic Lateral Sclerosis.
JO  - Molecular neurobiology
VL  - 60
IS  - 7
SN  - 0893-7648
CY  - Totowa, NJ
PB  - Humana Press
M1  - DZNE-2023-00449
SP  - 3898-3910
PY  - 2023
AB  - The fragile X protein (FXP) family comprises the multifunctional RNA-binding proteins FMR1, FXR1, and FXR2 that play an important role in RNA metabolism and regulation of translation, but also in DNA damage and cellular stress responses, mitochondrial organization, and more. FMR1 is well known for its implication in neurodevelopmental diseases. Recent evidence suggests substantial contribution of this protein family to amyotrophic lateral sclerosis (ALS) pathogenesis. ALS is a highly heterogeneous neurodegenerative disease with multiple genetic and unclear environmental causes and very limited treatment options. The loss of motoneurons in ALS is still poorly understood, especially because pathogenic mechanisms are often restricted to patients with mutations in specific causative genes. Identification of converging disease mechanisms evident in most patients and suitable for therapeutic intervention is therefore of high importance. Recently, deregulation of the FXPs has been linked to pathogenic processes in different types of ALS. Strikingly, in many cases, available data points towards loss of expression and/or function of the FXPs early in the disease, or even at the presymptomatic state. In this review, we briefly introduce the FXPs and summarize available data about these proteins in ALS. This includes their relation to TDP-43, FUS, and ALS-related miRNAs, as well as their possible contribution to pathogenic protein aggregation and defective RNA editing. Furthermore, open questions that need to be addressed before definitively judging suitability of these proteins as novel therapeutic targets are discussed.
KW  - Humans
KW  - Amyotrophic Lateral Sclerosis: genetics
KW  - Amyotrophic Lateral Sclerosis: metabolism
KW  - Neurodegenerative Diseases: genetics
KW  - RNA-Binding Proteins: genetics
KW  - Motor Neurons: metabolism
KW  - DNA Damage
KW  - RNA-Binding Protein FUS: genetics
KW  - Fragile X Mental Retardation Protein: genetics
KW  - Amyotrophic lateral sclerosis ALS (Other)
KW  - Amyotrophic lateral sclerosis ALS (Other)
KW  - Amyotrophic lateral sclerosis ALS (Other)
KW  - FMR1 FMRP (Other)
KW  - FXR1 FXR1P (Other)
KW  - FXR2 FXR2P (Other)
KW  - Neurodegenerative disease (Other)
KW  - Protein aggregation (Other)
KW  - RNA-Binding Proteins (NLM Chemicals)
KW  - RNA-Binding Protein FUS (NLM Chemicals)
KW  - FXR1 protein, human (NLM Chemicals)
KW  - FMR1 protein, human (NLM Chemicals)
KW  - Fragile X Mental Retardation Protein (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C2  - pmc:PMC10224833
C6  - pmid:36991279
DO  - DOI:10.1007/s12035-023-03330-x
UR  - https://pub.dzne.de/record/257569
ER  -