| ALS and frontotemporal dementia | Rare Neurological Diseases  

Hippocampal aggregation signatures of pathogenic UBQLN2 in amyotrophic lateral sclerosis and frontotemporal dementia

The central pathological hallmark of ALS is the presence of cytoplasmic inclusions or aggregates in degenerating motor neurons and surrounding oligodendrocytes. Inclusions are not restricted to the spinal cord but also present in other brain regions such as the frontal and temporal cortices, hippocampus and cerebellum.(3) The predominant aggregates found in ALS patients are ubiquitinated aggregates that are classified as either Lewy body-like hyaline inclusions or skein-like inclusions. (4) Thumbadoo et al (2) identified distinct patterns of UBQLN2 aggregation in the hippocampus. These patterns differentiate between mutant and wildtype UBQLN2, with mutant UBQLN2 showing a higher propensity to aggregate independently​. In addition to assessing the pathogenicity patterns of UBQLN2 variants, these findings are crucial for understanding how UBQLN2-linked neurodegeneration occurs.

Although it is well established that the pathology of ALS includes loss of motor neurons in the spinal ventral horns, most brainstem motor nuclei and motor cortex,  hippocampal involvement in ALS has been consistently highlighted by postmortem studies. (1) Hippocampal aggregation signatures of pathogenic UBQLN2 in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) refer to the specific patterns of protein aggregation observed in the hippocampus of individuals affected by these neurodegenerative diseases, UBQLN2 (ubiquilin-2) is a protein involved in the ubiquitin-proteasome system, which helps in the degradation of misfolded or damaged proteins. Mutations in UBQLN2 have been linked to familial forms of ALS and FTD, where abnormal protein aggregation plays a crucial role in the pathogenesis. UBQLN2 is involved in protein quality control by delivering ubiquitinated proteins to the proteasome for degradation. Mutations in UBQLN2 disrupt this function, leading to the accumulation of misfolded proteins and the formation of intracellular aggregates. These aggregates are toxic to neurons and are implicated in the neurodegenerative processes observed in ALS and FTD. The hippocampus is a critical brain region involved in memory and cognitive functions. In ALS and FTD, hippocampal neurons exhibit significant protein aggregation, including that of UBQLN2, however, its relationship to clinical manifestations including memory deficits remain unclear. It could be speculated that aggregation contributes to the degeneration of hippocampal neurons, leading to cognitive impairments and dementia symptoms in FTD, and, in some cases, cognitive decline in ALS. Pathogenic UBQLN2 can form distinct aggregates that can be identified using immunohistochemical techniques-using multiplexed (5-label) fluorescent immunohistochemistry. These aggregates often co-localize with other pathological proteins such as TDP-43, another protein commonly implicated in ALS and FTD. These signatures provide insights into the molecular mechanisms underlying disease progression.
Conclusion
In conclusion, the Authors (2) describe a hippocampal protein aggregation signature that fully distinguishes mutant from wildtype ubiquilin 2 in amyotrophic lateral sclerosis with or without frontotemporal dementia, whereby mutant ubiquilin 2 is more prone than wildtype to aggregate independently of driving factors. This neuropathological signature can be used to assess the pathogenicity of UBQLN2 gene variants and to understand the mechanisms of UBQLN2-linked disease. Research into the hippocampal aggregation signatures of pathogenic UBQLN2 in ALS and FTD highlights the critical role of protein misfolding and aggregation in these diseases. Identifying these specific aggregation patterns not only improves our understanding of the disease mechanisms but also holds promise for developing targeted therapies and improving diagnostic accuracy.

Key Points:

  • In ALS and FTD, the hippocampus, which is essential for memory and cognitive functions, shows significant protein aggregation. However, its relationship to clinical manifestations including memory deficits, remains not clear. These aggregates primarily include UBQLN2 and frequently co-localize with other pathological proteins such as phosphorylated TDP-43 and p62​
  • Advanced research techniques, such as multiplexed fluorescent immunohistochemistry, have identified distinct patterns of UBQLN2 aggregation in the hippocampus. These patterns differentiate between mutant and wildtype UBQLN2, with mutant UBQLN2 showing a higher propensity to aggregate independently​
  • Study (2) involving various ALS and FTD cases, including those with UBQLN2 mutations, have shown that pathogenic UBQLN2 variants lead to unique aggregation signatures. These findings are critical for assessing the pathogenicity of UBQLN2 variants and elucidating the mechanisms of UBQLN2-linked neurodegeneration​

References:

  1. 1.Christidi F, Karavasilis E, Rentzos M, et al. Hippocampal pathology in amyotrophic lateral sclerosis: selective vulnerability of subfields and their associated projections. Neurobiol Aging. 2019;84:178-188. doi:10.1016/j.neurobiolaging.2019.07.019
  2. Thumbadoo KM, Dieriks BV, Murray HC, et al. Hippocampal aggregation signatures of pathogenic UBQLN2 in amyotrophic lateral sclerosis and frontotemporal dementia. Brain. Published online May 4, 2024. doi:10.1093/brain/awae140
  3. Al-Chalabi A, Jones A, Troakes C, King A, Al-Sarraj S, van den Berg LH. The genetics and neuropathology of amyotrophic lateral sclerosis. Acta Neuropathol. 2012;124:339–352. doi: 10.1007/s00401-012-1022-4.
  4. Blokhuis AM, Groen EJ, Koppers M, van den Berg LH, Pasterkamp RJ. Protein aggregation in amyotrophic lateral sclerosis. Acta Neuropathol. 2013;125(6):777-794. doi:10.1007/s00401-013-1125-6

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