Neurological diseases Flashcards
Alzheimer’s disease
• Alzheimer’s disease is a major cause of dementia in the elderly.
__________ are accumulations of insoluble aggregates of amyloid beta peptide
Plaques
Alzheimer’s disease is characterized by ______________ and ____________
Plaques and tangles
APP processing and the formation of AB peptide
• Amyloid precursor protein (APP) processing and formation of AB peptide
As the diseases get more and more severe the plaques and tangles become ________
Worse
Alzheimer’s disease and synpases
Two majors themes that are important
Impaired spatial learning and memory in a transgenic mouse model of Alzheimer’s disease
• in the morris water maze the wt mouse is able to find the platform faster with repeated trials
_____________ is important in learning and memory
Presenilin
Exogenous Amyloid Beta reduces dendritic spines and LTP in hippocampal sites
• Looking at the effect of applying amyloid (AB) peptides on neurons and its effects on dendrites
In the presence of AB peptide there is a reduction in ____________________ _______________ on dendrites
Dendritic spines
____________ impairs LTP
Amyloid beta peptide
_______________ not required for LTP
Caspase 3
Appplying the AB peptide reduced the number of dendritic spines and impaired LTP so it is likely AB peptide is acting through _____________ to ____________LTP
Caspase 3 to Impair LTP
Presenilins
• The presenilin genes harbors mutations linked to early-onset familial Alzheimer’s disease (FAD), but how these mutations cause the disease is still being debated.
Presnilins regulate synaptic function
Presenilins conditionally knocked out in mice
___________ is involved in a number of effects in pre and post synaptic
Presenilin
when presenilin is removed there is _________________ in Ca induced Ca release which can affect NT release, pair pulse facilitation and facilitation
Reduction
Postsynaptic presenilin can effect ho much ______ receptors are expressed on the post synaptic terminal which can have an effect on ________
NMDA, LTP
How does presenilin regulte Ca induced Ca release
How does presilin regulate Ca induced Ca release
Pathogenic hypothesis for synaptic and neuronal toxicity in alzheirmenrs diseases
• AB amyloid hypothesis
Fragile X syndrome
• Fragile X syndrome (FXS), a heritable intellectual and autism spectrum disorder (ASD), results from the loss of
Fragile X syndrome gets worse as you ___
age
Fragile X mental retardation proteins
• In a normal condition the releases of CGGs; in a normal individual there are about 5-55 of CGG repeats
fragile X: the mGluR theory
• Stimulation of mGluR5 by glutamate induces local mRNA translation at the synapse.
GABAergic signalling is rescued in FMR1 knockout mice; this could be due to…..
Effects on GABA receptors as well as various enzymes that make and break down GABA as well as various transporters that take up GABA
Altered synapse formation and dendritic spine morphology in FXS
Can also have these effects on synapse formation and dendritic spine morphology
Huntington’s disease
• HD is caused by a CAG repeat expansion in the gene encoding the protein huntingtin (Htt); 35 polyglutamine repeats or more lead to HD, with longer repeats being associated with earlier disease onset.
Huntingtons______________over time
Progresses
In huntingtons disease you have _______________________ impairment that gets progressively worse
Motor/cognitve
Motor diagnosis is more apparent when the person is _____ of age
45 years
Huntingtons structures and transformations
gene structures of the HTT gene
Pathogenic cellular mechanisms in Huntingtons diseases
One cellular level
HTT fragments form due to _________ ______________
CAG repeats
HTT fragments has effects leading to _____________________________,________________________________ and ________________________
synaptic dysfunction, mitochondrial toxicity, and axonal transport impairments
Huntingtons disease overview
• Control: we have a glutamatergic neuron releasing glutamte, glutamate binds to AMPA and NMDA receptors leading to phosphorylation of CREB and it has effects on transcription and translation on various genes important in synapses.
Parkinson’s Disease
• Parkinson Disease (PD) is a neurodegenerative disorder affecting between 2-3 % of the population aged 65 or older.
Parkinson’s disease gets worse as the individual _________
Ages
Parkinson’s disease—Inherited mutations
• a-Synuclein
a-Synulclein
Genetic studies of Parkinson’s Disease began with the discovery of pathogenic missense mutations in the gene SNCA that encodes α-synuclein, a protein that is expressed throughout the brain and has potential roles in learning, synaptic plasticity, vesicle dynamics and dopamine synthesis.
Leucine-rich repeat kinase 2 (LRRK2)
• Leucine-rich repeat kinase 2 (LRRK2) has recently been implicated in Parkinson’s Disease and is thought to be involved in synaptic vesicle cycling and synaptic plasticity.
Parkin
• Mutations in the parkin gene (PARK2) have been linked to Parkinson’s Disease.
PTEN-induced kinase 1 (PINK1)
• Mutations in PINK1 have differential effects on protein stability, localization and kinase activity
DJ1
• DJ1 seems to have essential roles in dopaminergic neuronal transmission and reward that is mediated by the dopamine D2 receptor.
Parkinson’s disease overview
• If we start with synculin we have a mutation in SNCA gene that encodes for synulcin
Amyotrophic lateral sclerosis
• Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease, is primarily characterized by the degeneration of both upper and lower motor neurons, which leads to muscle weakness and eventual paralysis.
Mutations in several genes implicated in ALS exert motor neuronal injury though multiple mechanisms
• A lot of things happening—leads to mitochondrial disfunction, oxidative stress, impaired protein homeostasis, effects on DNA and RNA
