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Spinal Muscular Atrophy, TBI, Stroke, and Lysosomal Storage Diseases: Key Concepts, Exams of Nursing

Saddleback College Nursing

A comprehensive overview of key concepts and mechanisms related to spinal muscular atrophy (sma), traumatic brain injury (tbi), stroke, and lysosomal storage diseases. It delves into the causes, symptoms, and potential treatments for these neurological conditions, highlighting the role of genetics, stem cell transplantation, and lysosomal function. The document also explores the use of ipscs and brain organoids as models for studying these diseases. It is a valuable resource for students and researchers interested in understanding the complexities of these neurological disorders.

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N172 FINAL EXAM QUESTIONS WITH 100% CORRECT

ANSWERS

Spinal muscular atrophy (SMA) -- Answer ✔✔ - serious and typically fatal neurological

disease that attacks the nerve cells that control voluntary muscles - only affects lower

motor neurons

- entirely genetic therefore pediatric disease (effects kids at young age): autosomal

recessive

- caused by progressive degeneration of motor neurons in the spinal cord and brainstem

- causes progressive weakness and wasting of the voluntary muscles

- sma is caused by mutations or deletions in the gene SMN (survival in motor neurons)

What is severity of SMA dependent on? -- Answer ✔✔ how much SMN protein you are

producing

genetics of SMA -- Answer ✔✔ - two SMN genes and three types of SMA

- normally two copies of SMN gene: SMN 1 is the main gene, SMN2 is backup gene

-disease is primarily caused by the loss of or conversion of SM1, but varying levels of

SMN2 can partially compensate - when you inherit two bad copies from parents

(deletion of both copies of SMN1), only making about 20% of proteins - Type 1 SMA

(MOST SEVERE)

- Type 2 SMA - when only inherit one bad copy, one SMN1 lost and duplication of

SMN2 - maintain 30% production of SMN proteins

- Type 3: two duplications of SMN2 gene - makes about 40% SMN protein (least severe)

modeling SMA by deleting one or two copies of the mouse SMN gene -- Answer ✔✔ -

remove both copies - severe effects

- remove one copies - a little better, still stunted growth

Are there other ways to model SMA? -- Answer ✔✔ used iPSC

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N172 FINAL EXAM QUESTIONS WITH 100% CORRECT

ANSWERS

Spinal muscular atrophy (SMA) -- Answer ✔✔ - serious and typically fatal neurological disease that attacks the nerve cells that control voluntary muscles - only affects lower motor neurons

entirely genetic therefore pediatric disease (effects kids at young age): autosomal recessive
caused by progressive degeneration of motor neurons in the spinal cord and brainstem
causes progressive weakness and wasting of the voluntary muscles
sma is caused by mutations or deletions in the gene SMN (survival in motor neurons) What is severity of SMA dependent on? -- Answer ✔✔ how much SMN protein you are producing genetics of SMA -- Answer ✔✔ - two SMN genes and three types of SMA
normally two copies of SMN gene: SMN 1 is the main gene, SMN2 is backup gene
disease is primarily caused by the loss of or conversion of SM1, but varying levels of SMN2 can partially compensate - when you inherit two bad copies from parents (deletion of both copies of SMN1), only making about 20% of proteins - Type 1 SMA (MOST SEVERE)
Type 2 SMA - when only inherit one bad copy, one SMN1 lost and duplication of SMN2 - maintain 30% production of SMN proteins
Type 3: two duplications of SMN2 gene - makes about 40% SMN protein (least severe) modeling SMA by deleting one or two copies of the mouse SMN gene -- Answer ✔✔ - remove both copies - severe effects
remove one copies - a little better, still stunted growth Are there other ways to model SMA? -- Answer ✔✔ used iPSC

differentiation of SMA iPSCs into motor neurons
looking to see if we see that motor neurons with this mutation are more likely to die in a dish?
results: when SMA iPSCs are differentiated into motor neurons, less survive, and surviving MNs are smaller Can SMA iPSC cells be used to identify drugs that might help treat SMA? -- Answer ✔✔
SMA iPSCs have fewer nuclear "germs" containing SNM protein. Treatment with HDAC inhibitors (opens up chromatin and allows for more transcription) that increase transcription partially restore SNM levels Traumatic Brain Injury -- Answer ✔✔ - silent epidemic
#1 killer of children and young adults in the US
TBI affects 1.7 million Americans per year
more than brain, breast, colon, lung and prostate cancer combined Primary causes of TBI -- Answer ✔✔ - falls
motor vehicle accidents
assault
struck by object symptoms of mild TBI -- Answer ✔✔ - No loss of consciousness, or loss <30 min
Headaches
Dizziness
Concentration problems
Forgetting things
Irritability
Fatigue
Sleep problems
Balance
problems
Ringing in the ears
Vision changes

impactor can provide a digitally controlled impact on the skull
most is done on closed head injuries
leads to degeneration, loss of brain tissue How might stem cell transplantation help to treat TBI? - replace lost neurons -- Answer ✔✔ Neurons within the dentate gyrus of the hippocampus appear to be particularly vulnerable to TBI - This is one of two areas where adult neurogenesis occurs
provide growth factors that may help nearby damaged neurons to survive or promote synaptic plasticity to compensate for lost connectivity
replace lost oligodendrocytes - remyelination of diffuse axonal injury How might stem cell transplantation help to treat TBI? - modulate neuroinflammation -- Answer ✔✔ - mesenchymal stem cells (MSCs) can be derived from bone marrow, adipose tissue (fat), umbilical cord
MSCs can self-renew and differentiate into fibroblasts, chondrocytes, adipocytes, and osteoblasts
MSCs have been shown to secrete a variety of immune-modulating proteins and exosomes Why implant bone marrow into the brain? -- Answer ✔✔ - very safe type of cell - can self renew a few cycles but don't last very long
can be isolated from a patient and put back into same patient - very adaptable for an autologous approach Brain organoids -- Answer ✔✔ - a new way to model human brain development and perhaps even TBI
this is an approach that allows one to, starting with pluripotent stem cells and then deriving them towards a neural lineage, you can actually get these sort of three- dimensional structures to spontaneously form.
if using hPSC, every organoid you produce is human
organoids can be placed in phantom skull and then subjected to a controlled impact Stroke - ischemic (most common) -- Answer ✔✔ blockage of blood vessels, could be due to clot, starves tissue of blood supply (often unilateral

common initial symptoms of stroke -- Answer ✔✔ There are some symptoms that are quite common in stroke and one of the key symptoms of stroke is it can be quite sudden onset. So sudden problems with vision, blurriness, double vision, sometimes problems with understanding speech or speaking, paralysis of an arm or a leg. exact symptoms is dependent on where in the brain is the blood supply blocked off Strokes - hemorrhagic -- Answer ✔✔ rupture of blood vessels; going to impair the supply of blood downstream from that area where the injury is. But it also has the added problem in that you can have a leakage of that blood into the surrounding tissue and that can put pressure on the tissue. And also there are some quite inflammatory molecules within the blood itself that the brain is not normally exposed to that can promote further damage. Ischemic stroke: embolism -- Answer ✔✔ embolism - where you have a clot that is essentially traveled. It's come loose and traveled up that artery until it becomes lodged blocking off the blood supply to everything above it Ischemic stroke: thrombosis -- Answer ✔✔ a clot that is kind of built up more gradually on the wall of that brain or artery. current treatment of ischemic stroke -- Answer ✔✔ if we can have a way to dissolve that clot, we might be able to restore blood supply to that area of the brain and limit the amount of cell death that occurs tPA - tissue plasminogen activator, and it's essentially a concentrated form of something our own body makes for dissolving clots. And if it's provided soon after the symptoms, typically in less than four and a half hours, it can break up that clot, help to restore some of that blood supply, and reduce the damage What would happen if you treat a hemorrhagic stroke with tPA? -- Answer ✔✔ tPA promotes blood supply so this would make a hemorrhagic rupture worse since you would want clotting to stop the bleeding

why are neurons especially susceptible to lysosomal storage diseases? -- Answer ✔✔ - neurons can't divide and they can't dilute out the accumulating substrates

we don't make new neurons throughout the brain so we can't replace those that die Sandhoff's Disease -- Answer ✔✔ - lysosomal storage disease
heterozygous autosomal recessive
results from loss-of-fxn of an enzyme beta-hexosaminidase leading to toxic accumulation of GA2 and GM
on avg 1 in 4 kids of carrier parents are effected Sandhoff's symptoms -- Answer ✔✔ Symptoms:
can appear normal until about 6-months when child starts to show regression of developmental milestones
muscle weakness, blindness, deafness, inability to react to stimulants, respiratory problems and infections, mental retardation, seizures, enlarged liver and spleen
most children with Sandhoff' die by 3 years of age current treatments of Sandhoff's -- Answer ✔✔ - only symptomatic and supportive treatments are currently available
supportive treatments includes proper nutrition and hydration and keeping the airway open
anticonvulsants may be used to control seizures Just injecting a replacement of the missing enzyme won't work for the major neurological symptoms of Sandhoff's. Why? -- Answer ✔✔ - enzyme won't cross the BBB Deletion of Beta-hexosaminidase models Sandhoff’s disease and neural stem cell transplantation of neonates improves survival -- Answer ✔✔ - NSCs mice lifespan extended by a little
preserved motor fxn for 16-18 weeks mouse NSCs integrate robustly into the neonatal Sandhoff's mouse model brain -- Answer ✔✔ - mNSC differentiate into neurons, astrocytes, and oligodendrocytes

Transplanted mNSCs increase beta-hexosdaminidase levels and decrease GM2 and GA2 gangliosides (partial reduction)
microglial reactivity (sign of inflammation) is reduced in NSC-transplanted mice human NSC found similar results as mNSC in Sandhoff's -- Answer ✔✔ hCNS-derived and hES-derived (human embryonic stem cell) NSCs also improve survival and motor function + reduce GM2 and GA2 concentrations why is there only a partial improvement in survival and fxn? -- Answer ✔✔ although you doubled Beta-hexosaminidase, only were able to go from 2% to 4% which is not enough also adding NSC that can degrade the buildup, but the other neurons still can't - cross- correction cross-correction -- Answer ✔✔ most of the lysosomal enzymes travel from the Golgi to the lysosome within the transplanted cells. Only a small proportion of the fxl enzyme is secreted by the NSCs and taken up by the host neurons
some of the enzymes from the NSC are leaking out and getting endocytosed by the host neuron and goes to lysosomes - > very low in conc that leak out tho so not as effective Gaucher Disease -- Answer ✔✔ - most frequent lysosomal disease
25% of affected child in autosomal recessive
cell that is most effected is macrophages (a part of innate immunity, cousin of microglia) which are important for turnover of red blood cells
in GD, lysosomes are incapable of degrading lipids in RBCs, accumulation of fat-filled lysosomes Link btwn GD and Parkinson’s -- Answer ✔✔ patients who are carriers have 4x likelihood to get Parkinson’s

typically a fatal neurological disease that attacks the nerve cells that control voluntary muscles (both upper and lower motor neurons degenerate)
voluntary movement progressively lost as motor neurons stop sending messages to the muscles
cognitve, sensory, and emotional abilities rarely affected ALS Symptoms -- Answer ✔✔ - muscle weakness in one or more of the following: hands, arms, legs or the muscles of speech, swallowing or breathing (usually what kills them)
twitching and cramping of muscles, especially those in the hands and feet
impairment of the use of the arms and legs
"thick speech" and difficulty in projecting the voice who gets ALS? -- Answer ✔✔ - typically ALS develops btwn the ages of 35-70, but can also begin during the teenage years or twenties
lifetime risk 1 in 1,
60% of those with the disease are men
93% are Caucasian'
10% of patients have an effected patient Why do motor neurons selectively degenerate in ALS? -- Answer ✔✔ - motor neurons are larger and have extremely long axonal projections
larger size requires greater metabolic production: more mitochondria, increased oxidative stress, increased need for growth factors
selective uptake - unique receptors on motor neurons may allow specific uptake of some toxins causes of ALS -- Answer ✔✔ - inherited (familial) ALS - up to 1 in 10 cases of ALS. 20% of these cases result from a specific gene mutation in an enzyme known as syperoxide dismutase 1 (SOD1) (mutations impairs function + causes it to aggregate)
other inherited ALS genes: TDP-43, FUS, angiogen, c9orf72 (strongest correlation with ALS)
sporadic ALS - 90% Risk factors for ALS -- Answer ✔✔ - environmental factors

food, dietary neurotoxin (Guam)
extensive physical activity
pesticide and agricultural chemicals
industrial chemicals and medical drugs
genetic factors
aging Theories of Mutant SOD toxicity -- Answer ✔✔ - oxidative-stress hypothesis: mutant SOD does not deal with reactive superoxides very well (gain of function - more free radicals accumulating, motor neurons become more vulnerable)
aggregation hypothesis: mutant SOD clumps into toxic protein aggregates modeling ALS -- Answer ✔✔ - transgenic mice or rats expressing mutant SOD
model actually mimics this motor neuron death quite nicely and really does show us, yes, superoxide dismutation mutations can drive motor neuron death and lead to pretty much all the symptoms you see in ALS Stem cell and ALS -- Answer ✔✔ - too difficult to replace lost motor neurons
can protect or repair effected endogenous motorneurons
model the disease; iPSCs generation and validation of neural progenitor cells that overexpress GDNF -- Answer ✔✔ - modified the cells to make more GDNF using lentivirus
unilateral transplantation of GDNF-NPCs (neural progenitor cells) and in vivo production of GDNF
unilateral model used since there is a localized effect so can deliver one version of the cells on one side and the other version on the other sides
side where they delivered cells, seems to be a lot more GDNF
GDNF-NPCs increase survival of motorneurons
only as good as the distribution capabilities of the cells

one-sided conversation repetitive motor mannerisms lack of spontaneous social play Asperger's syndrome: Little professors -- Answer ✔✔ lack of empathy little ability to form friendships one sided convo intense absorption in special interest clumsy movement Birth trauma is a risk factor of autism -- Answer ✔✔ - anemia ~8x

inhaled meconium ~7x
weak crying after birth ~5x refrigerator theory of autism -- Answer ✔✔ parents of autistic children "just happening to defrost enough to produce a child" genetic factors in autism -- Answer ✔✔ - very strong
autism is highly heritable as shown by the high concordance in monozygotic twins (70- 90%)
one sibling with disease increases likelihood by 25-fold
age of father or his father (grandpaternal) at conception increase risk (~2-fold) presumably due to accumulated spontaneous mutations ASD conditions that arise from single gene dysfunction -- Answer ✔✔ - rett syndrome
fragile x syndrome
timothy syndrome rett syndrome -- Answer ✔✔ - hand wringing, no verbal skills, stereotyped movement
mostly in girls (boys die very early)
linked to mutations in the MeCP2 gene

DSM-V has now separated from autism spectrum disorders Fragile X syndrome -- Answer ✔✔ retardation in most, autism like symptoms in some Timothy syndrome -- Answer ✔✔ heart arrhythmia and autism symptoms (developmental delay) mutations in CACNA1C, a subunit of a voltage gated calcium channel Gentamicin - drug discovery using patient iPS cells -- Answer ✔✔ - common antibiotic that is also toxic to certain mammalian sensory cells such as hair cells in inner ear

enahcnes the translation of MeCP2 protien
restores synapse density along dendrite of neurons derived from Rett patient iPS cells MeCP2 gene -- Answer ✔✔ a transcription factor that regulates many other genes and is expressed in all brain cells
mutations in gene linked to Rett syndrome mutations in CACNA1C -- Answer ✔✔ linked to Timothy syndrome nimopdipine - drug discovery using iPSC -- Answer ✔✔ calcium channel blocker that corrects the abnormally long action potentials in Timothy syndrome patient derived neurons action potentials in patients with Timothy syndrome -- Answer ✔✔ abnormally long lasting (4ms instead of 3ms) main diff btwn als and sma -- Answer ✔✔ - sma is solely genetic disease
only affects lower motor neurons, not both upper and lower why are more of the early clinical studies of SC transplantation and antisense oligonucleotide therapies being pursued in rarer diseases such as ALS and SMA? -- Answer ✔✔ - fda looking at risk vs reward
bc the diseases are so fatal, ppl are more eager to try novel and risky therapies

retention of more age-related epigenetic changes (these changes influence the ability for a gene to be transcribed or not) - good for studying age-related diseases age-related epigenic changes -- Answer ✔✔ - can use measurements of these epigentic changes to accurately predict someone's age comparing fibroblast aging genes (direct reprogramming) vs ipsc aging genese -- Answer ✔✔ epigenetic marks and age-related changes in gene expression are erased during the iPSC reprogramming process
researchers then made iNs from the same 18 fibroblasts that were used to make the iPSCs
little overlap btwn the age-related genes founds in fibroblasts and those found in iNs Why might diff genes be on for the age-relate genes found in fibroblasts vs the age- related genes found in iNs derived from that fibroblast? -- Answer ✔✔ cell types are also defined by the differing epigenetics that either activate or repress sets of genes that are needed for that Cell's differentiation, identity, and function so, in each cell type, a subset of a cell-specific active genes may also be further altered by age-related epigenetic changes (the added changes of being a neuron and the aging epigenetics is what makes for a diff set of genes that are changed with age than a fibroblast) some of the altered genes in iNs pointed towards impairments in nuclear-cytoplasmic compartmentalization (NCC) -- Answer ✔✔ exp: designed a system to monitor nuclear important and export and thereby quantify NCC deficits
GFP with a nuclear export signal (NES)
RFP with a nuclear import/localization signal (NLS)
therefore, in a normal functioning system GFP expressing genes should be outside the nucleus and RFP expressing genes inside the nucleus
if NCC is disrupted, then more RFP will stay in the cytosol and more GFP will stay in the nucleus what did they see?

fibroblasts from older patients exhibit worsening nuclear-cytoplasmic compartmentalization (NCC)
iNs made from older patients also exhibit worsening NCC - > effect is actually much worse on the iNs then on the fibroblasts
but NCC is not altered in iPSC from the same aged patients Are there any drawbacks to iNs vs neurons that are differentiated from iPSCs? -- Answer ✔✔ - fibroblasts have limited capacity to divide so the number of iNs one can make is also quite limited contrasted to being able to make endless supply from iPSCs
direct reprogramming exhibits variable efficiency and so one often doesn't have a pure population of neurons to study (Can use FACs to help purify a set of cells) Can you also make other cell types from fibroblasts? -- Answer ✔✔ yes - for ex) made astrocytes can we reprogram cells in vivo? -- Answer ✔✔ yes but reprogramming of astrocytes to neurons is more efficient in younger mice ALSP -- Answer ✔✔ - primary microglialopathy (driven by microglial dysfunction)
encompasses any disease involving microglial dysfunction and CSFR1 gene (gene is expressed solely in microglia and border-associated macrophages)
causes about 15% of all leukodystrophies (white matter disease!!)
progressive disease characterized by disruptions in executive function, memory impairments, changes in judgement and personality and motor impairments and seizures mutations that cause ALSP -- Answer ✔✔ - associated with CSF1R mutations
majority occur within the kinase domain and cause a reduction in downstream CSF1R signaling (likely to be loss of function disease)
dominant mutation
theories:
haploinsufficiency: lose one copy of the gene, and get the disease bc you don't have enough of the gene copy
dominant negative: mutation in a gene can disrupt the function of the normal version of the gene, tends to be more common in proteins that bind to each other (for example CSF1R needs to two copies to dimerize be active receptor)
both theories seem to be at play

exhibited increased white matter autofluoresnecne and mylein basic protein (MBP) levels that are strongly correlated exhibit increased accumulation of the disease-associated oligodendrocyte protein Sepina3n within the white matter why is there thicker white matter seen in FIRE mice? -- Answer ✔✔ - no microglia means no myelin turn over - just accumulating

later will have the loss of myelin and white matter thinning what is the impact of transplanting ALSP-patient derived iPSC-microglia (iMGs) into FIRE mice after the onset of pathology? -- Answer ✔✔ can crispr mediated correction of ALSP mutations alter these results? -- Answer ✔✔ yes - benefit would be autologous treatment CRISPR corrected ALSP3-microglia rescue disease-associated deficits in microglial proliferation, have fully engrafted microglia, and reduce pre-existing axonal spheroid pathology while uncorrected IPSC mice have limited engraftment and fail to reduce brain calcification Frontotemporal Dementia -- Answer ✔✔ a group of disorder that cause progressive nerve cell loss in the frontal and temporal loves of the brain How many FTD cases are familial and caused by mutations in specific genes? -- Answer ✔✔ 30% mutations in these genes:
C9orf
Progranulin (GRN)
Tau (MAPT) C9orf72 gene -- Answer ✔✔ Most common mutations in FTD and ALS (indicates this is a risk gene)

Highly associated with TDP-43 pathology Progranulin (GRN) -- Answer ✔✔ Secreted protein that regulates lysosomal function

60 mutations that result in haploinsufficiency microglia have the highest levels of progranulin in the brain Tau (MAPT) -- Answer ✔✔ Microtubule stabilizing protein Families with mutations nearly always have history of FTD example of disease where two copies of a gene gives you lysosomal storage disease but one copy gives you neurodegenerative disease -- Answer ✔✔ one copy GBA = parkinsons two copies = gauchers what did we see in FTD mice with human iPSC-microglial progenitors? -- Answer ✔✔ - reduced neuropathology

increased microglia engraftment
reduction in autofluorescent lipofuscin accumulation within the thalamus New drug clinical trials: phase 1 -- Answer ✔✔ - checking for safety
20 - 100 volunteers
1st state of testing in humans New drug clinical trials: phase 2 -- Answer ✔✔ - checking for efficacy
100 - 500 patients
how well does the drug work? new drug clinical trials: phase 3 -- Answer ✔✔ - confirm results (replicate)
1000 - 5000 patients
drug must be safe
comparison with current gold standard treatment New drug clinical trials: phase 4 -- Answer ✔✔ - FDA review // phase 4 trials

Spinal Muscular Atrophy, TBI, Stroke, and Lysosomal Storage Diseases: Key Concepts, Exams of Nursing

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N172 FINAL EXAM QUESTIONS WITH 100% CORRECT

ANSWERS