Neurodegeneration - What is Neurodegeneration?

Neurodegeneration is the umbrella term for the progressive loss of structure or function of neurons, including death of neurons.

Many neurodegenerative diseases including Parkinson’s, Alzheimer’s, and Huntington’s occur as a result of neurodegenerative processes.

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.

There are many parallels between different neurodegenerative disorders including atypical protein assemblies as well as induced cell death.

Neurodegeneration can be found in many different levels of neuronal circuitry ranging from molecular to systemic.

The greatest risk factor for neurodegenerative diseases is aging. Mitochondrial DNA mutations as well as oxidative stress both contribute to aging

Protein degradation offers therapeutic options both in preventing the synthesis and degradation of irregular proteins. There is also interest in upregulating autophagy to help clear protein aggregates implicated in neurodegeneration. Both of these options involve very complex pathways that we are only beginning to understand.

Genetics

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. Diseases showing this are known as polyglutamine diseases.

Polyglutamine: A repeat in this causes dominant pathogenesis. Extra glutamine residues can acquire toxic properties through a variety of ways, including irregular protein folding and degradation pathways, altered subcellular localization, and abnormal interactions with other cellular proteins
- Nine inherited neurodegenerative diseases are caused by the expansion of the CAG trinucleotide and polyQ tract. Two examples are Huntington's disease and spinocerebellar ataxias. While polyglutamine-repeat diseases encompass many different neurodegenerative disorders, there are many more it does not apply to. The genetics behind each disease are different and often unknown.

alpha-synuclein: can aggregate to form insoluble fibrils in pathological conditions characterized by Lewy bodies, such as Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. Alpha-synuclein is the primary structural component of Lewy body fibrils. In addition, an alpha-synuclein fragment, known as the non-Abeta component (NAC), is found in amyloid plaques in Alzheimer's disease.

Intracellular mechanisms

Protein degradation pathways

Parkinson’s disease and Huntington’s disease are both late-onset and associated with the accumulation of intracellular toxic proteins. Diseases caused by the aggregation of proteins are known as proteinopathies, and they are primarily caused by aggregates in the following structues:

Axonal transport

Axonal swelling and spheroids have been observed in many different neurodegenerative diseases. This suggests that defective axons are not only present in diseased neurons, but also that they may cause certain pathological insult due to accumulation of organelles. Axonal transport can be disrupted by a variety of mechanisms including damage to: kinesin and cytoplasmic dynein, microtubules, cargoes, and mitochondria.

Programmed cell death

Programmed cell death (PCD) is death of a cell in any form, mediated by an intracellular program. There are, however, situations in which these mediated pathways are artificially stimulated due to injury or disease.

Caspases (cysteine-aspartic acid proteases) cleave at very specific amino acid residues. There are two types of caspases: initiators and effectors. Initiator caspases cleave inactive forms of effector caspases. This activates the effectors which in turn cleave other proteins resulting in apoptotic initiation.