Journal of Clinical Pathology and Laboratory Medicine

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Mini Review - Journal of Clinical Pathology and Laboratory Medicine (2023) Volume 5, Issue 1

Amyotrophic lateral sclerosis new molecular pathology pathways.

Sandra Elizabeth*

Department of Pathology,University Medical Centre Utrecht, Netherlands.

*Corresponding Author:
Sandra Elizabeth
Department of Pathology
University Medical Centre Utrecht

Received:28-Dec-2022, Manuscript No. AACPLM-23-85204; Editor assigned:31-Dec-2022, PreQC No. AACPLM-23-85204(PQ); Reviewed:13-Jan-2023, QC No. AACPLM-23-85204; Revised:19-Jan-2023, Manuscript No. AACPLM-23-85204(R); Published:27-Jan-2023, DOI:10.35841/aacplm-5.1.133

Citation: Elizabeth S. Amyotrophic lateral sclerosis new molecular pathology pathways. J Clin Path Lab Med. 2023;5(1):133


The severe degenerative condition known as Amyotrophic Lateral Sclerosis (ALS) is characterised by the gradual loss of motor neurons in the motor cortex, brainstem, and spinal cord. Frontotemporal lobe dementia can develop along with ALS, despite the latter's classification as a motor condition. ALS starts out focally but spreads to cause paralysis and eventual death. Gene mutations cases and ALS-related genes have been found. Investigations of ALS genes have identified pathogenic roles for: (a) perturbations in protein stability and degradation, (b) altered homeostasis of crucial RNA- and DNA-binding proteins, (c) impaired cytoskeleton function, and (d) non-neuronal cells as modifiers of the ALS phenotype.


Amyotrophic Lateral Sclerosis (ALS), Neuron death, Protein aggregation, Super Oxide Dismutase (SOD).


The progressive, fatal condition known as Amyotrophic Lateral Sclerosis (ALS) affects motor neurons and causes weakening in the muscles of the limbs, airways, and bulba. Nearly all limbs and respiratory function, as well as the capacities to chew, swallow, and talk, are lost in the moments before death. Frontotemporal lobar dementia and familial ALS (fALS) or sporadic ALS (sALS) might manifest at the same time. While memory loss is the hallmark of Alzheimer's disease (AD) dementia, FTLD is marked by behavioural abnormalities and increasing aphasia, occasionally accompanied by mobility difficulties. While the hippocampus shows substantial pathology in AD, the frontal and temporal lobes show early atrophy in FTLD, as the term implies[1].

From the pathological investigation of autopsied patients of sALS, fALS, or ALS-FTLD with various genetic origins, four consistent themes have been identified. First, the deposition of aggregated proteins, frequently ubiquitinated and predominately cytoplasmic, occurs frequently after motor neuron death. Second, RNA and RNA-binding proteins exhibit aberrant amounts and functions in ALS. Both motor neurons and non-neuronal cells, like astrocytes and microglia, contain protein and RNA aggregates. Third, the majority of cases involve some disruption of the structure and operation of the neuronal cytoskeleton. Additionally, non-neuronal cells, such as oligodendroglia and cells engaged in neuro-inflammation, virtually always have an impact on motor neuron death[2].

Several species of protein are defective in both fALS and sALS, as demonstrated by the formation of aggregates, atypical cleavage events, or specific posttranslational modifications, which is a key motif in the ALS pathogenesis. Both the direct effects of the afflicted proteins' mutations and the secondary effects brought on by the underlying illness process contribute to these changes. Aggregation of proteins and inclusion bodies. It has long been known that protein pathology plays a significant role in ALS, as shown by an early pathological finding of the build-up of ubiquitinated material in motor neurons. According to one interpretation, this indicates the presence of proteins that are changed or conformational unstable and are therefore headed for disintegration[3].

Mutant SOD1 toxicity has a complex and evasive molecular underpinning. Mutant SOD1 most likely causes oxidative stress because SOD1 detoxifies superoxide anion. When SOD1 is zinc-depleted, a condition that speeds up misfolding, this is exacerbated. Second, poisonous nitrotyrosines can be produced by mutant SOD1. Abnormal cellular copper and zinc buffering and trafficking is a third contributor to SOD1 disease. The ability of the unstable mutant SOD1 protein to bind to objects with hydrophobic surfaces-to which WT SOD1 is less adherent—is a fourth feature. Regardless of the molecular mechanisms behind their cytotoxicity, mutant versions of SOD1 have the ability to impair a variety of cellular processes[4].

The majority of times in sALS, fALS, and FTLD, hyper phosphorylated, cleaved TDP-43 builds up sporadically in the cytoplasm of neurons and glia, where it congregates form rounded, thread-like inclusions. These abnormal TDP-43 forms first become visible in spinal motor neurons before spreading laterally into the brain and the CNS. Recently, TDP-43 was discovered to be a part of cytoplasmic deposits in a variety of neurodegenerative disorders. TDP-43 may have lost its role in the nucleus, acquired an unfavourable effect from its abnormal presence in the cytoplasm or both, as evidenced by the depletion of TDP-43 from the nucleus in various illnesses[5].


Accessing the CNS is always tricky while treating ALS. The blood-brain barrier guards the brain and spinal cord and prevents many small chemicals and macromolecular treatments from entering the body. Finding sensitive ALS biomarkers and identifying ALS quickly enough to allow for early intervention are two additional significant obstacles in ALS therapy. Despite these obstacles, it is promising that there has been significant advancement in identifying the genetic variables that affect ALS risk and phenotype. The fundamental events converging on numerous downstream processes are implicated in each of the more than 40 ALS genes that have recently been discovered. Potential treatment targets for each ALS gene are disclosed. Because the majority of ALS genes are dominantly transmitted, they are expected to be cytotoxic due to inherited traits that reduce the viability of motor neurons. Some of these, like SOD1 and C9orf72, exhibit dose-dependent disease, where the severity of the phenotype increases with the number of mutant gene products. This suggests that methods to mute the problematic mutant genes might be advantageous. Fortunately, there are a number of novel methods for silencing genes, including tiny, intrathecal administered antisense oligonucleotides and adeno-associated viral vectors that carry both shRNA and artificial miRNAs to the CNS.


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