Neurodegen 4 Flashcards
Common pathological features in NDD
1) Impaired proteostasis due to failure in the
ubiquitin-proteasome system, autophagy
and/or lysosomal systems
2) Mitochondrial dysfunction
3) Failure of mitochondrial biogenesis related to
impaired mitophagy.
4) Tau hyperphosphorylation
5) Prionoid propagation of misfolded proteins
Impaired proteostasis leads to
Accumulation of misfolded proteins, with oligomers exhibiting greater toxicity than larger aggregates (microscopically visible aggregates may represent an attempt to insolubize and thus limit the cell damage)
Toxic oligomers cause:
Mitochondrial dysfunction
With increased generation of superoxide and downstream ROS. This situation results in both increased oxidative stress and ATP depletion
Cellular pathology due to mitochondrial mitochondrial dysfunction is exacerbated in
Taupathies, including AD, due to impaired microtubule-based axonal transport of mitochondria to energy hotspots at nodes or synapses
What leads to prionoid propagation
Release and reuptake of toxic proteins by adjacent cells
What can lead to NDD
Any condition that impairs either proteostasis or mitochondrial turnover can lead to NDD
Initial sites of pathology and classes of neurons showing dysfunctionin particular NDDs are probably determined by what factors
- Dependence of a particular class of neuron on the protein targets of the NDD eg Huntingtin in HD or a synuclein in PD
- The morphology of the affected neurons: cells with long axons are vulnerable in different NDDs and may be more affected by the mitochondrial and microtubule based transport defects that are a common feature of almost all NDDs. Significantly in ALS, MN tend to have long axons and dysfunction of th e target protein SOD-1 is likel to exacerbate superoxide toxicity in their mitoschondria
- The firing activity of the particular neurons in their local subsystem (local energy demands - same issues apply as in 2)
Describe firing activity as a factor of NDD
neurons most severely affected in
Parkinson’s disease, the dopaminergic neurons of the substantia nigra,
exhibit an autonomous pacemaker activity, meaning that they undergo
continuous cycles of exo- and endocytosis all throughout their life, thus
placing particular importance on the maintenance and regulatory
functions of α-Synuclein
What determines work load and exposure to toxic protein
Position within local network and density of connections determines
both work load (recent study showed that in the cortical system under
study, 70% of the information passed through only 20% of the cells),
and exposure to toxic protein spread in their subsystem
Describe neurons within the default-mode network
appear to be involved in episodic memory processing, which is distinguished by reduced activity in Alzheimer’s disease compared to healthy aging.
Recent studies suggest that β-amyloid deposition in the DMN occurs earlier than in other systems affected in Alzheimer’s disease.
Targeting the generation of toxic proteins as therapeutic approaches for NDDS
1) Stimulation or correction of deficits in the ubiquitin-
proteasomal system
2) Enhancement or correction of autophagic and lysosomal
mechanisms
3) Kinase inhibitors to inhibit generation of
hyperphosphorylated Tau
4) Disease-specific interventions such as BACE inhibitors in
Alzheimer’s to reduce the production of β-amyloid
(includes MABs targeting BACE), or LRRK2 in Parkinson’s.
5) Therapeutic antibodies that scavenge misfolded proteins
from the extracellular space , especially toxic oligomers,
thus preventing re-uptake by affected neurons and
PRIONOID propagation to unaffected cells.
Describe the modern increase in incidence of NDDs: life style factors
Sedentary occupations and general lack of exercise.
Obesity and carbohydrate-based diet rich in refined
sugars that drive insulin receptor signalling.
Uninterrupted supply of nutrition.
1) All of the above depress autophagy and mitochondrial
turnover (turnover includes both mitophagy and
mitochondrial biogenesis).
2) All lifestyle factors associated with longevity and
retardation of NDD have been shown to increase
autophagy: physical exercise, ketogenic diets, calorific
restriction or periodic fasting.
Describe the mTOR signalling hub
Links over-nutrition to suppression of autophagy
In order to grow and divide, cells must increase production of proteins, lipids, and nucleotides while also suppressing catabolic pathways such as autophagy. The mTOR kinase and it’s associated signaling hub, mTORC1, plays a central role in regulating these processes in response to environmental conditions.
Excessive insulin-receptor signalling, driven by refined carbohydrates and constant availability of amino acids leads to mTOR-mediated suppression of autophagy.
Inhibition of mTOR with the drug, rapamycin increases autophagy and is currently the only pharmacological treatment conclusively proven to extend lifespan in model organisms (Drosophila, C Elegans & Mice). However, there is increasing evidence that Metformin, a drug used to reduce insulin resistance and hepatic gluconeogenesis in type-2 diabetes shows similar effects via indirect inhibition of mTOR.
What is metformin
Diabetes drug with potential to inhibit ageing
Describe the mechanism of chaperone-mediated autophagy
Proteins degraded by CMA are identified in the cytosol by a chaperone complex that,
upon binding to the targeting motif in the substrate protein, brings it to the surface of
lysosomes.
Binding of the substrate to the cytosolic tail of the receptor protein LAMP-2A promotes
LAMP-2A multimerization to form a translocation complex.
Upon unfolding, substrate proteins cross the lysosomal membrane assisted by a luminal
chaperone and reach the lysosomal matrix where they undergo complete degradation.
