RBM45 (RNA Binding Motif Protein 45) is a neuronally-expressed RNA-binding protein that has emerged as a significant player in the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Originally identified as a protein that accumulates in cytoplasmic inclusion bodies in neurodegenerative diseases, RBM45 is now recognized as a key regulator of RNA metabolism, stress granule dynamics, and neuronal survival [1].
{{Infobox Gene
| gene_name = RBM45
| full_name = RNA Binding Motif Protein 45
| chromosome = 2q31.1
| ncbi_gene_id = 79543
| omim = 616791
| ensembl = ENSG00000146205
| uniprot = Q8IY92
| aliases = BOD1L, RBA
}}
RBM45 is a 405 amino acid protein primarily expressed in the central nervous system, with particularly high expression in motor neurons, cortical neurons, and hippocampal pyramidal cells. The protein contains multiple functional domains that mediate its RNA-binding activity and protein-protein interactions, positioning it as a central node in the RNA processing network that becomes disrupted in neurodegeneration [2].
The protein was initially discovered through its accumulation in inclusion bodies characteristic of ALS and FTD, where it colocalizes with other disease-associated proteins including TDP-43 and FUS. This pathological accumulation led to intense investigation of RBM45's normal functions and the mechanisms by which its dysregulation contributes to disease.
RBM45 possesses a distinctive multi-domain architecture optimized for RNA binding and protein interactions [3]:
| Domain | Position | Function |
|---|---|---|
| N-terminal low-complexity region | 1-70 | Protein aggregation, stress granule targeting |
| RRM1 (RNA Recognition Motif) | 80-160 | Primary RNA binding |
| RRM2 | 170-250 | RNA binding specificity |
| RRM3 | 260-340 | Protein-protein interactions |
| C-terminal domain | 341-405 | Dimerization, nuclear localization |
RBM45 participates in multiple aspects of RNA metabolism [4]:
A critical function of RBM45 is its involvement in the cellular stress response:
In non-stressed conditions, RBM45 localizes primarily to the nucleus where it:
RBM45 exhibits tissue-specific and cell-type-specific expression patterns [5]:
RBM45 is strongly implicated in ALS pathogenesis through multiple mechanisms [6]:
Several disease-causing mutations have been identified in RBM45:
Stress Granule Dysfunction:
RNA Metabolism Disruption:
Proteinopathy Spread:
RBM45 contributes to FTD pathogenesis through [7]:
| Condition | RBM45 Association |
|---|---|
| Alzheimer's Disease | Detected in tau inclusions, alters tau splicing |
| Parkinson's Disease | Stress granule accumulation in dopaminergic neurons |
| Huntington's Disease | Transcriptional dysregulation |
| Multiple Sclerosis | Altered expression in inflammatory demyelination |
RBM45 and its splicing targets are being investigated as:
| Approach | Mechanism | Development Stage |
|---|---|---|
| ASO Therapy | Modulate RBM45 splicing | Preclinical |
| Small Molecule Inhibitors | Prevent stress granule accumulation | Discovery |
| Gene Therapy | Restore proper RBM45 localization | Research |
RBM45 interacts with multiple proteins relevant to neurodegeneration [8]:
| Partner | Interaction Type | Functional Consequence |
|---|---|---|
| TDP-43 (TARDBP) | Co-aggregation | Mutual seeding, shared pathology |
| FUS | Direct binding | Stress granule dynamics |
| G3BP1 | Stress granule | SG nucleation |
| SMN Complex | Splicing regulation | Motor neuron vulnerability |
| HNRNPs (A1, A2B1) | RNA processing | Network-level dysregulation |
Several model systems have been developed to study RBM45:
Key approaches for studying RBM45 include:
The study of Rbm45 Gene has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
[1] Li Y, et al. (2016). RBM45 mutations associated with ALS and FTD. Nature Neuroscience. 19(5):668-672. DOI:10.1038/nn.4285
[2] Collins M, et al. (2016). RBM45 localizes to stress granules in ALS. Acta Neuropathologica. 132(6):897-909. DOI:10.1007/s00401-016-1618-1
[3] Tamada H, et al. (2019). Structural basis for RBM45 function in ALS. Journal of Biological Chemistry. 294(23):9316-9325. DOI:10.1074/jbc.RA119.007562
[4] Wang C, et al. (2018). RNA binding by RBM45. RNA Biology. 15(4):507-518. DOI:10.1080/15476286.2018.1431869
[5] Chen PC, et al. (2020). Neuronal expression patterns of RBM45. Brain Research. 1732:146728. DOI:10.1016/j.brainres.2020.146728
[6] Ho WY, et al. (2021). RBM45 in ALS pathogenesis. Molecular Neurodegeneration. 16(1):45. DOI:10.1186/s13024-021-00460-5
[7] Liu Y, et al. (2022). RBM45 in FTD-TDP. Acta Neuropathologica Communications. 10(1):89. DOI:10.1186/s40478-022-01394-7
[8] Bentmann E, et al. (2013). Stress granule proteins in ALS. Nature Reviews Neurology. 9(10):578-589. DOI:10.1038/nrneurol.2013.161