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.
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.
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
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
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
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