Spinocerebellar Ataxia type 2 – background of the disease (research) and potential treatments

Due to a family in which 3 children suffer from SCA2, I researched the genetic background behind this hereditary disease and found potential therapeutic approaches that could possibly be used “off-label – repurposed – as an individual healing attempt”.

Summary at the beginning

Wheat probably plays a negative role, because the more gliadin antibodies there are, the worse the course.

Due to mutations, different “ataxia 2 proteins” are formed that clump together (=amyloid), these protein clumps lead to nerve cell apoptosis via the protein unfolding system (PUS). A mechanism quite similar to that in Alzheimer’s and other neurodegenerative diseases with protein clump formation (Parkinson’s, chorea, …)!

• Influencing the UPS can influence the course of the disease:Trazodone 
• Influencing autophagy can influence the course of the carbohydrates: Spermidine, curcumin, resveratrol, 
• Influencing clumping can influence the course of the carbohydrates: Melatonin, NAC
• Improved flushing of the brain can influence the course of the carbohydrates: Lithium, zolpidem

Neuromodulation improves – Testimonial

wonderful improvement of gait, stuttering, tremor – walked in TRIPOD-gait and is now able to walk Heal-Toe (!!!!) – Neurologist and Physiotherapist are excited and confirm improvement just as all her friends. Talks better. 25. Febr 2025 Praxis Dr. Retzek

OK, let’s go into detail

Exact genetic background

Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant inherited neurodegenerative disease. The genetic disorder that causes SCA2 affects the ATXN2 gene, which is located on chromosome 12q24.1. The mutation in this gene consists of an expansion of a trinucleotide repeat sequence (CAG).

this gene sequence is disrupted, resulting in proteins that have “long amino acid tails”

In healthy individuals, this CAG repeat is normally found 13 to 31 times in the ATXN2 gene. However, in individuals suffering from SCA2, this repeat is expanded to 32 to 200 times or more. The number of repeats usually correlates with the severity and age of disease onset: the more repeats, the earlier the disease appears and the more severe the symptoms.

this makes the protein poorly soluble and “precipitates” into “amyloid plaques”

The extended CAG repeat results in an extended glutamine sequence in the ataxin-2 protein. The mutated protein tends to accumulate in aggregates and disrupts the normal function of nerve cells, particularly in the cerebellum and brain stem. This leads to the typical symptoms of SCA2, including ataxia, dysarthria and slowly progressive loss of muscle coordination.

the pathomechanism is “protein unfolding system”

I researched this in my article about Trittico and Alzheimer’s: when such plaques (= dirt deposits) lie around in the tissue, the affected cells try to escape this pollution by

• first inhibiting the formation of new proteins
• improving the correct folding of proteins with “chaperones” = “HSP70”
• finally the cell dies “to be on the safe side” so as not to clutter up the rest of the brain with its protein clumps —> Apoptosis

too many clumps: the cells die

The protein unfolding system plays a role in the pathogenesis of spinocerebellar ataxia type 2 (SCA2) and the formation of ataxin-2 aggregates. Protein unfolding systems, also known as protein quality control systems, are cellular mechanisms responsible for detecting, repairing or degrading misfolded proteins to prevent cellular stress and dysfunction.

therapeutic influence on the protein unfolding system

There are approaches and compounds that influence the protein unfolding system and may be therapeutically effective in neurodegenerative diseases. Some examples include:

1. Chaperone molecules: Cchaperone proteins, such as HSP70, HSP90 and small heat shock proteins, are involved in the recognition and degradation of misfolded proteins. Modulating these chaperone proteins can help improve the folding and stability of proteins and reduce the occurrence of protein aggregates. – I am not aware of any available therapy that can induce heat shock proteins – except hyperthermia
2. Proteasome inhibitors: The proteasome is a cellular machinery that is responsible for the degradation of misfolded proteins. Proteasome inhibitors, such as bortezomib and carfilzomib, can modulate the function of the proteasome and thus influence the balance between protein production and the degradation of misfolded proteins.
3. Autophagy modulators: Autophagy is a cellular process that contributes to the elimination of misfolded proteins and protein aggregates. Activating autophagy by compounds such as rapamycin or metformin can help reduce the accumulation of misfolded proteins and the formation of aggregates. These include, for example, spermidine, metformin, ….
4. Antioxidants and anti-inflammatories: Oxidative stress and inflammation can contribute to the misfolding of proteins and the formation of aggregates. Antioxidants and anti-inflammatory compounds, such as N-acetylcysteine, curcumin or resveratrol, can reduce cellular stress and thus support the protein unfolding system. These include, for example, curcumin, resveratrol, …
5. In fact, there are some studies that suggest that trazodone (Trittico) may have some benefit in the treatment of neurodegenerative diseases by influencing apoptosis through the protein unfolding system.

let’s go through each approach

readily available autophagy inducers

spermidine

Spermidine is a naturally occurring polyamine found in many foods and plays a role in cell regulation. Spermidine has been shown to induce autophagy and in some studies shows potential health benefits in the treatment of age-related diseases and neurodegenerative disorders.

Although there are no direct studies examining the effect of spermidine on ataxin-2 aggregates in spinocerebellar ataxia type 2 (SCA2), its ability to promote autophagy could theoretically help reduce the accumulation of ataxin-2 aggregates and improve cellular function in SCA2 patients.

Since spermidine induces autophagy, it may have a similar mechanism to other autophagy activators such as rapamycin, which has been shown in some studies to reduce ataxin-2 aggregation and cellular toxicity in cell culture and Drosophila models of SCA2.

The potential of spermidine as a treatment option is promising, but there are no clinical trials in SCA2 patients.

Now the “knowledgeable” person will of course immediately ask himself

how easily does spermidine cross the blood brain barrier

Gupta, V. K., et al. (2013) “Restoring polyamines protects from age-induced memory impairment in an autophagy-dependent manner”. Nature Neuroscience, 16(10), 1453-1460. Link: https://doi.org/10.1038/nn.3512

In this study, the authors investigated the effects of spermidine on aging and memory in Drosophila and mouse models. It shows that spermidine is effective in the brain and influences aging processes and memory function there; the mouse model is highly likely to be transferable to humans.

Other Substances Associated with Autophagy Induction in the Brain

There are several substances known as autophagy inducers that have been shown in studies to be able to promote autophagy in the brain. Some of these readily available substances include:

1. Resveratrol: A natural compound found in grapes, berries, and nuts. Resveratrol has been shown to induce autophagy and may have neuroprotective effects in neurodegenerative diseases.
2. Curcumin: A bioactive component of turmeric, a spice commonly used in Indian cooking. Curcumin has antioxidant and anti-inflammatory properties and may promote autophagy in the brain.
3. Fisetin: A naturally occurring flavonoid compound found in strawberries, apples, and other fruits. Fisetin has antioxidant properties and has been shown to promote autophagy in various cell types, including nerve cellsn, to induce.
4. Quercetin: A flavonoid found in many fruits and vegetables such as apples, onions and green tea. Quercetin has antioxidant and anti-inflammatory properties and can promote autophagy in cell cultures and animal models.
5. Sulforaphane: A bioactive compound found in cruciferous vegetables such as broccoli, Brussels sprouts and cauliflower. Sulforaphane has antioxidant and anti-inflammatory properties and has been shown to induce autophagy in various cell types.

I did some of this research with Chat-GPT, e.g. “give me 10 diseases where PUS plays a central role”-

What else could be done: flushing the brain

The brain cells shrink by 60% at night – the smaller nerve cells leave a gap through which cerebrospinal fluid is pushed through and protein clumps are flushed away. A disruption of this “glymphatic system” always leads to weaknesses in brain function.

I have now found some simple means and medications that can be used to stimulate this flushing – this is important for each of us, I’ll save it for a separate article.

Testing an SCA2 patient

It’s very exciting that the patient is probably constitutionally Calc-carb and that the SCA-2 or ataxin-2 gene is a calcium channel that no longer functions properly and lets too much calcium into the cells. Causticum, a homeopathic remedy for brain degenerative processes, also tested very well. The rest of the remedies are self-explanatory from the studies shown above.