User:Rcchang16/sandbox

Pathophysiology
While there may be obvious environmental, viral, toxic, or genetic causes, most cases of Motor Neuron Disease are idiopathic or unknown.

ALS, the most common Motor Neuron Disease, is thought to be a multifactorial disease. Several proposed mechanisms that contribute to this debilitating neurodegenerative disease include oxidative stress, excitotoxicity, damage to key cellular processes including axonal transport, mitochondrial dysfunction, protein aggregation. transcriptional regulation, and mRNA processing. The final step in the complex neurodegenerative process is thought to be through programmed cell death resembling caspase-dependent apoptosis. Only a small subset of ALS is hereditary (5-10%). Of these small cases, most are autosomal dominant. Implicated genes include SOD1, Dynactin p150 subunit (DCTN1), TARDBP, C9ORF72, ALSIN, Senataxin (SETX), Vesicle Associated Membrane Protein (VAPB), and Microtubule associated protein tau (MAPT).

These implicated genes provide clues to the mechanisms of ALS. SOD1 has been particularly illuminating in understanding the biology of this debilitating motor neuron disease. For example, SOD1 genetically encodes for a protein involved in protecting against oxidative stress, known to cause neuronal injury and implicated in neurodegenerative diseases. The protein SOD1 is abundant in the central nervous system, particularly in motor neurons. In addition, SOD1 mutant models have increased sensitivity to glutamate toxicity, through (1) alterations of the number of receptors (AMPA receptors) that respond to glutamate release in the synpase and (2) proteins (EAAT2) that take up glutamate from the synapse. The dynein and dynactin complex is an important motor protein for transport along microtubules, which are part of "the cellular highway." Mutations in this complex cause progressive ALS in mice and mutations in the Dynactin p150 subunit (DCTN1) are associated with vocal cord paralysis in humans.

In cellular models of SOD1, the mitochondria are markedly increased and impaired ability to produce ATP due to altered mitochondrial protein production. These studies are complemented by human ALS studies that similarly demonstrate mitochondrial dysfunction including (1) alterations in mitochondrial morphology in liver, muscle, and motor neurons, (2) multiple mutations and decreased mitochondrial DNA, and (3) altered electron transport chain activity.

Similar to other neurodegenerative disease, ALS also has been associated with aggregation of misfolded proteins. In SOD1 mutant mice, protein inclusions are found in the cytoplasm of motor neurons as well as astrocytes, which develop before the onset of motor dysfunction. These protein inclusions could theoretically cause cellular toxicity through (1) sequestration of proteins required for normal motor neuron function, (2) removal of chaperone proteins responsible for folding essential proteins, (3) reducing the function of a large protein complex (proteaseome) essential for protein turnover, and (4) impairing the function of organelles particularly mitochondria.

In a small subset of hereditary ALS cases (5%), mutations in TARDBP have been found. This gene encodes TDP-43, an RNA binding protein, which is important for transcriptional regulation and mRNA processing. Subsequent work revealed that mutations in other RNA processing proteins including TBP-associated factor 15 (TAF15), heterogenous nuclear ribonucleoportein A1 (hnRNPA1) and A2B1 (hnrNPA2B1). Thus defects in RNA processing have been implicated in ALS. In these patients, TDP-43 positive protein inclusions have been found. The most common mutation found in hereditary ALS cases, C9ORF72, found in 43% of patients also has cytoplasmic TDP-43 positive inclusions. Interestingly, there is an expansion of GGGGCC repeats in this genetic region or loci, like trinucleotide repeat expansion diseases like Huntington's Disease. Unfortunately the role of the encoded C9ORF72 protein is unknown.

There is also evidence that non-neuronal cells including microglia are involved in ALS. Microglia play a role in phagocytosis and release of cytotoxic molecules including ROS, nitric oxide, proteases, and proinflammatory signaling molecules (cytokines) including TNF alpha, IL-6, and Interleukin-1B, Interestingly, activated microglia are a prominent histologic feature in mutant SOD1 transgenic mice as well as human ALS. Interestingly, there is also elevated inflammatory cytokines upregulated in the spinal cord or CSF in human patients with ALS including IL-6, IL-1B, COX2, and prstaglandin E2. This finding highlights the role of inflammation in the disease.

Human autopsy tissue from ALS patients strongly suggest that the final step of neuronal cell death is through programmed cell death pathway that closely resembles normal apoptosis. Histologic evidence includes increased TUNEL staining that detects DNA fragmentation, increased expression of apoptosis related molecules, alterations in the Bcl2 family of proteins towards an overall apoptotic signal, and significant increases in caspase 1 and 3 activity in the spinal cord.

Environmental factors including diet and cigarette smoking are associated with ALS. Dietary toxins including lathyrism (from chickling peas) and konzo (unprocessed) cassava, have resulted in spastic paraparesis. Genetic association studies demonstrate an increased risk of ALS with cigarette smoking (Odds ratio of 1.6).

Timeline
Article: Motor neuron disease

By mid-Week 1 (11/28):

* Kokinishimura:

* rcchang16: attend Wikipedia course introduction and complete tutorials. draft a timeline of my workplan and submit to neuroteam!

* Khemphill1:

By end of Week 1 (12/1):

* Kokinishimura:

* rcchang16: compile initial references for Pathophysiology and Terminology

* Khemphill1:

By mid-Week 2 (12/5):

* Kokinishimura:

* rcchang16: Finalize references for Pathophysiology and Terminology

* Khemphill1:

By end of Week 2 (12/8):

* Kokinishimura:

* rcchang16: Begin initial drafts including 2 figures - one for UMN vs. LMN. and pathophysiology mechanisms. Prepare for meeting with group on 12/9.

* Khemphill1:

By mid-Week 3 (12/12):

* Kokinishimura:

* rcchang16: Finalize first draft of text and figures for review.

* Khemphill1:

By end of Week 3 (12/15):

* Kokinishimura:

* rcchang16: Begin discussion with team members about edits and prepare for peer review. Start peer preview of other article.

* Khemphill1:

By mid-Week 4 (12/19):

* Kokinishimura:

* rcchang16: Incorporate peer review comments and finalize figures and draft. Begin to reflect on course.

* Khemphill1:

By end of Week 4 (12/21):

* Kokinishimura:

* rcchang16: Reflect on course at last WIP meeting.

* Khemphill1:

Practice Header
Starting spot - UCSF Be bold! Trying to be bold!