Neurodegeneration is the umbrella term for the progressive loss of structure or function of neurons, including death of neurons. Neurodegenerative diseases constitute one of the major challenges of modern medicine, including Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, Lyme disease, Parkinson's disease, and so on. These diseases are relatively common and often highly debilitating. However, the mechanisms responsible for their pathologies are poorly understood, and there are currently no effective preventative therapies. As research progresses, many similarities appear which relate these diseases to one another on a sub-cellular level. Discovering these similarities offers hope for therapeutic advances that could ameliorate many diseases simultaneously. Recent research on the genetic pathways leading to pathology with animal models (mice and Drosophila) begun to identify molecular mechanisms underlying neurodegenerative disorders.
Many neurodegenerative diseases are caused by genetic mutations, most of which are located in completely unrelated genes. In many of the different diseases, the mutated gene has a common feature: a repeat of the CAG nucleotide triplet. CAG encodes for the amino acid glutamine. A repeat of CAG results in a polyglutamine (polyQ) tract. Research on the neurodegenerative disease, spinocerebellar ataxia type 1 (SCA1), found out that polyglutamine expansion contributes to disease by both a gain-of-function mechanism and partial loss of function of the SCA1 encoded protein ATXN1. Another important pathological mechanism is alpha-synuclein aggregation. Alpha-synuclein is the primary structural component of Lewy body fibrils. Normally an unstructured soluble protein, alpha-synuclein can aggregate to form insoluble fibrils in pathological conditions characterized by Lewy bodies, such as Parkinson's disease, dementia with Lewy bodiesand multiple system atrophy. Alpha-synuclein pathology is also found in both sporadic and familial cases with Alzheimer's disease.
Strong evidence underscores the tight link between oxidative stress and neurodegenerative disease pathogenesis, including in four of the well known diseases Alzheimer's, Parkinson's, Amyotrophic lateral sclerosis, and Huntington's. Studies suggest that oxidative modification of K+ channels might be a general principle underlying aging and neurodegeneration. The formation of intracellular aggregates by toxic proteins is also a cause of many late-onset neurodegenerative diseases, including Parkinson's disease and Huntington's disease. The degradation pathways acting on such aggregate-prone cytosolic proteins include the ubiquitin-proteasome system and macroautophagy. Dysfunction of the ubiquitin-proteasome or macroautophagy pathways might contribute to the pathology of various neurodegenerative conditions. In addition, current research indicates that cell death in neurodegeneration is generally due to apoptosis and most commonly through the intrinsic mitochondrial pathway.