2.2.1. Trinucleotide Repeat Expansion Disorders

The expansion of microsatellite repeats is the cause of several neurodegenerative diseases. They are usually caused by replication errors such as polymerase dissociation or arrest, or sliding of the 5 and or 3 ends of the Okazaki fragment, which results in the formation of a hairpin structure [60,61]. Neurodegenerative diseases that are classified as trinucleotide repeat expansion disorders (TREDs) are caused by the repetition of the CNG sequence (where N is one of the 4 nucleotides) in certain genes. These disorders can further be subclassified as PolyQ (where the repeated sequence CAG encodes glutamine), like Huntington's disease (HD), and Spinocerebellar Ataxia types 1, 2, 3, 6, 7, 12, 17, and non-PolyQ (where other triplets are repeated), like myotonic dystrophy (DM) or Friedreich's ataxia (FRDA) [62,63].

#### 2.2.2. Huntington's Disease Etiology

Huntington's disease is a rare disorder of the CNS. It affects 5–10 in 100,000 people [64]. It is the most common disorder in Europe and USA, and the least in Asia [65–67].

HD symptoms include uncontrolled body movements, weight loss, facial grimaces, psychological disorders, personality changes, and apathy. First non-specific symptoms can start 10 years before full manifestation of HD, which usually occurs between 35 and 40 years of age. The disease can also affect juveniles, but it is extremely rare in patients under the age of 10 and over the age of 70. The life expectancy after first symptoms is 15–20 years, with the most common causes of death being aspiration pneumonia, heart disease, and suicide [68–70]. The mutation that causes HD is located in the first exon of the *HTT* gene and is inherited in an autosomal dominant manner. In healthy individuals, the first exon contains between 10 and 35 CAG repeats, and the disease severity varies depending on the number of repeats: 27–35 repeats do not cause the disease but increase the probability of HD manifestation in progeny; 36–38 repeats cause the disease with incomplete penetrance; and more than 39 repeats cause the disease with complete penetrance, where the first symptoms occur in patients at the age of 40–55. More than 60 repeats cause the juvenile form, where the first symptoms occur before the age of 21 [71]. This specific mutation in *HTT* leads to the expression of mutant HTT (mHTT) protein, which tends to form intracellular insoluble aggregates that are the pathologic hallmark of HD [72]. The longer the polyQ repeats, the more aggregates it forms. In the brain, the disease pathology is linked to neuronal loss in the striatum, which is responsible for control of motor functions and the reward center. Medium spiny neurons make up the structure of the striatum, and these cells are mainly affected by pathogenic mHTT aggregates, which lead to neuronal loss and secondary gliosis. The other hallmarks of HD pathology are weight loss, gastritis, esophagitis, and nutritional deficiencies, all of which point to a strong link with dysfunction of the digestive tract. mHTT has been found to be expressed in the majority of tissues, including the gastrointestinal tract. Interestingly, studies performed on mouse models have shown that mHTT forms aggregates in the enteric nervous system even before neurological and motoric symptoms appear. It has also been reported that HD affects the functions of the gastrointestinal (GI) system through impaired gut motility, diarrhea, and malabsorption of food, and even influences the gut anatomy by reducing mucosal thickness and villus length, as well as the loss of various neuropeptides that stimulate or inhibit gut motility [73]. There are also pathological changes in gene transcription—mHTT aggregates have been found to interact with several proteins involved in various transcriptional pathways. They have been found to interact with specificity protein 1 (SP1), CREB-binding protein (CBP), peroxisome proliferator-activated receptor-γ coactivator 1α (PGC1α), Nuclear factor κ light-chain-enhancer of activated B cells (NF-κB), and Repressor element 1 (RE1)-silencing transcription factor (REST) [74]. Altered transcription in HD is also linked to mitochondrial

dysfunction. Diminished transcription of PGC1α negatively impacts energy metabolism and mitochondrial biogenesis. The mHTT has also been found to have a strong association with the translocase of mitochondrial inner membrane 23 (TIM23) complex, which impairs protein import and disrupts mitochondrial function [74–76].
