Journal of Clinical & Experimental Pathology
Open Access

Degeneration of motor neurons in the brain and spinal cord causes Amyotrophic Lateral Sclerosis (ALS), a progressive neurodegenerative illness that eventually results in paralysis, muscle weakness. About 10% of ALS cases are hereditary and are linked to known genetic mutations, whereas the majority of ALS cases are spontaneous. It is essential to comprehend how these genetic alterations impact neuropathological results in order to clarify the causes of disease, better diagnosis, and create targeted treatments. Many genetic mutations have been linked to ALS, and each one contributes differently to the pathophysiology of the illness. The most frequent genetic cause of Frontotemporal Dementia (FTD) and a family history of ALS is the C9orf72 gene mutation, which involves a Hexanucleotide Repeat Expansion (G4C2). This mutation causes Repetition-Associated Non-ATG (RAN) translation, which results in the synthesis of hazardous dipeptide repeat proteins. Neuropathological manifestations in individuals harboring C9orf72 (Chromosome 9 Open Reading Frame 72) mutations encompass broad TDP-43 (Transactive response DNA binding protein of 43) proteinopathies, motor neuron loss, and frontal and temporal lobe degeneration. Compared to other hereditary variants of ALS, the C9orf72 mutation is linked to an earlier onset and a more severe course of the disease. Notable findings include the presence of spongiosis and neurofibrillary tangles in the frontal and temporal brain.

When the Superoxide Dismutase 1 (SOD1) gene is mutated, a misfolded protein is produced; this builds up and results in oxidative stress. The death of motor neurons is connected to this sedimentation. Motor neuron cytoplasmic inclusions, misfolded SOD1 aggregates, and oxidative damage are among the neuropathological features of SOD1-related ALS. Certain SOD1 mutations cause early-onset and quickly progressive types of ALS, while other mutations are linked to a varied disease start and course. One characteristic of this mutation is the existence of SOD1-positive inclusions. TDP-43 is a protein involved in RNA processing that is encoded by the TAR DNA-binding protein 43 (TARDBP) genes. TDP-43 mislocalizes and aggregates in the cytoplasm as a result of mutations in TARDBP. There are signs of neuroinflammation and ubiquitinated TDP-43 inclusions in the cytoplasm of glial and motor neurons, among other neuropathological abnormalities. Mutations in TDP-43 are frequently linked to ALS and FTD. The central nervous system is more widely involved when TDP-43 inclusions are present, impacting both motor and non-motor areas. A protein involved in RNA processing and DNA repair is encoded by the Fused in Sarcoma (FUS) gene. The FUS protein aggregates cytoplasmically when there is a mutation in the FUS gene.

FUS-positive inclusions in motor neurons and astrocytes, as well as TDP-43 inclusions, are among the neuropathological characteristics of FUS-related ALS. Fast-progressing and juvenile-onset types of ALS are linked to FUS mutations. One characteristic that distinguishes this genetic subgroup is the existence of FUS-positive inclusions.

The pathophysiology of ALS is also influenced by mutations in the Angiogenin (ANG) and Ubiquilin-2 (UBQLN2) genes. While UBQLN2 mutations impact protein degradation pathways, ANG mutations impair motor neuron function by causing abnormalities in protein homeostasis. Motor neuron loss and aberrant protein aggregation are examples of neuropathological findings. Depending on the exact mutation and how it affects protein function, ANG and UBQLN2 mutations are linked to a variety of onset ages and rates of illness progression. Motor neuron loss is present in all hereditary types of ALS; however the pattern and severity might differ. For instance, mutations in FUS and TARDBP may cause more focal degeneration, whereas mutations in C9orf72 and SOD1 frequently result in the loss of motor neurons throughout a large area. One feature of the neuropathology of ALS is protein aggregation. It is typical to find TDP-43, SOD1, and FUS inclusions in impacted motor neurons. These clumps impair regular cellular processes and fuel neurodegeneration. ALS also affects glial cells, such as microglia and astrocytes, in addition to motor neurons. Gene mutations such as C9orf72 and SOD1 cause neuroinflammation and glial cell activation, which worsen damage to motor neurons. In ALS, chronic neuroinflammation is a common characteristic. Neuroinflammation varies in type and degree depending on genetic alterations. FUS and C9orf72 mutations cause more marked inflammatory responses. Accurate diagnosis is improved by knowing how genetic mutations affect neuropathology. More accurate diagnosis and prognosis are made possible by genetic testing, which can identify carriers of mutations and shed light on the mechanisms underlying disease.

Targeted therapy development is aided by genetic knowledge. Clinical trials are being conducted, for instance, to investigate antisense oligonucleotide medicines that target certain mutations, including the C9orf72 repeat expansion. Furthermore, gene-editing tools and small compounds may be able to treat pathogenic processes that are particular to mutations. Treatment plans can be created by using genetic information to customize interventions based on the particular genetic mutation and the neuropathological traits it is associated with. The goal of ongoing research is to better understand the molecular pathways that genetic abnormalities in ALS influence. Research on cellular failure, neuroinflammation, and protein aggregation is essential for creating novel treatment approaches and comprehending the variability of disease.

A major factor influencing the neuropathological terrain of ALS is genetic mutation. These mutations offer significant information into the processes and course of the disease by affecting neuroinflammation, motor neuron degeneration, and protein aggregation. Improved diagnostics, targeted medicines, and individualized treatment plans are possible due to developments in genetic research and our growing understanding of neuropathological results. Further investigation into the relationship between genetic alterations and neuropathology is necessary to improve the diagnosis of ALS and create practical treatments for this severe condition.