The tau protein , a crucial factor in Alzheimer ’ s , may also play a role in Parkinson ’ s
March-April . 2024 | The HEALTH
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21
Unveiling the genetic arsenal
The tau protein , a crucial factor in Alzheimer ’ s , may also play a role in Parkinson ’ s
BRAIN BITES
BY DR WAEL MY MOHAMED
Dr Wael MY Mohamed is with the Department of Basic Medical Science , Kulliyyah of Medicine , International Islamic University Malaysia ( IIUM ).
ONE in five individuals has a gene that , albeit unknown , seems to protect against Alzheimer ’ s and Parkinson ’ s . Stanford Medicine researchers and colleagues found that a vaccination that slows or stops these two most frequent neurodegenerative diseases may assist these fortunate individuals even more .
An examination of medical and genetic data from hundreds of thousands of individuals of varied ancestries from many continents found that possessing this gene allele lowered Parkinson ’ s and Alzheimer ’ s risk by more than 10 per cent . Tau , a protein known for aggregating in Alzheimer ’ s sufferers ’ brains , may also be surprisingly implicated in Parkinson ’ s disease .
The results and consequences are in an online Proceedings of the National Academy of Sciences publication . The protective allele in the research is DR4 . A previous study indicated that the DR4 allele protected against Parkinson ’ s . The Stanford Medicine team merged hundreds of medical and genetic datasets from Europe , East Asia , the Middle East , and South and North America .
Over 100,000 Alzheimer ’ s patients and 40,000 Parkinson ’ s patients were in the databases . The researchers identified a 10 per cent risk decrease in Alzheimer ’ s and Parkinson ’ s incidence and age of start in those with DR4 . The researchers also examined the autopsied brains of over 7,000 Alzheimer ’ s patients . They found that DR4 carriers had fewer neurofibrillary tangles , long , filamentous aggregates made of tau , and a later onset of symptoms .
Neurofibrillary tangles greatly predict severity . Even though neurofibrillary tangles are rare in Parkinson ’ s , carrying DR4 was associated with a later start of symptoms . This research suggests that tau , a crucial factor in Alzheimer ’ s , may also play a role in Parkinson ’ s , but the exact involvement is unknown .
CELL SURFACES DISPLAY INFORMATION
DR4 is one of several alleles of DRB1 , a gene in the human lymphocyte antigen complex
( HLA ) that makes cells ’ inner contents apparent to the immune system . A cell ’ s outer membrane keeps its contents within and outside out . Beyond that , it does more .
The immune system sees protein fragments via its display window . Regular exposure of these pieces , or peptides , on the cell ’ s outer membrane permits wandering immune cells to browse them . These patrolling immune cells may check cell-surface peptides for foreign or altered proteins , indicating an infection or malignancy .
Window shopping is made easier by specialised proteins that collect and enclose all these peptides and display them on cell surfaces for immune identification . HLA genes produce these specialised proteins . Each HLA gene has several alleles .
Each person inherits distinct alleles . HLA alleles ’ protein products bind to distinct sets of peptides ; therefore , each person ’ s cells exhibit a particular immune surveillance peptide mix . In response to a new surface peptide , the immune system may launch a severe assault on any cell with it .
Mistaken identification occurs sometimes in judgements . Autoimmunity occurs . DR4 is implicated in “ protective autoimmunity ”: DR4 may exhibit a chemically modified tau peptide . Chemical alteration causes problems .
THE TAU LINK ?
DR4 improves tau levels and pathologies in Alzheimer ’ s and Parkinson ’ s , thus , researchers focused on tau . They cut the protein into 482 peptides covering tau ’ s full sequence and put them in separate plates with DR4 ’ s protein product ( DR4 ) to check whether it binds firmly to any of them .
The researchers then investigated all the physiologically plausible chemical alterations each peptide may undergo after cell production . DR4 gripped one peptide strongly . PHF6 , a tau protein fragment , is often acetylated in Alzheimer ’ s sufferers ’ brains .
Acetylated PHF6 is said to cause tau molecules to form neurofibrillary tangles . DR4 is only tightly linked to PHF6 when acetylated . PHF6 acetylation is known to promote tau aggregation into neurofibrillary tangles .
Acetylation may “ fool ” the immune system into believing PHF6 is a foreigner and a threat , causing it to attack and destroy neurofibrillary tangles . A vaccination may postpone or slow Alzheimer ’ s and Parkinson ’ s in patients who possess any of the protective versions of DR4 ( not all are protected ) and whose brains have started to build tau clumps .
This vaccination wouldn ’ t help non-DR4 carriers . DR4 has several subtypes with minor genetic variations . One of DR4 ’ s six or seven most frequent subtypes may be more prevalent in one lineage than another .
The DR4 subtype most frequent among East Asians doesn ’ t appear to prevent neurodegenerative illness as well as other subtypes . A blood test should be done to determine vaccination eligibility .
I consistently inspire my patients with these lines :
In the symphony of life , Parkinson ’ s adds a unique melody , reminding us that beauty can be found in every note , even those filled with struggle .
The sun may set , but it always rises again . Parkinson ’ s teaches us that there is always hope for a new dawn , even in our darkest moments . – The HEALTH