End Stages Of Huntington's Disease – William Harvey Research Institute, Barts and London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom.
Huntington’s disease (HD) is a severe, progressive and fatal autosomal recessive disorder. This condition is characterized by motor dysfunction (chorea in the first stage, followed by bradykinesia, dystonia and motor incoordination in the last stage), mental disorders and cognitive decline. The neuropathological symptom of HD is defined as neuronal loss in the striatum (caudate nucleus and putamen). The striatum is related to controlling movement, flexibility, motivation and learning and purinergic signaling plays an important role in controlling these phenomena. Purinergic signaling involves the actions of purine nucleotides and nucleosides through the activation of P2 and P1 receptors, respectively. External nucleotides and nucleoside-metabolizing enzymes regulate the levels of these messengers, modulating purinergic signaling. The striatum has a high expression of adenosine A
- 1 End Stages Of Huntington's Disease
- 1.1 A Biological Classification Of Huntington’s Disease: The Integrated Staging System
- 2 Timing And Impact Of Psychiatric, Cognitive, And Motor Abnormalities In Huntington Disease
End Stages Of Huntington's Disease
Receptors, which are involved in the neurodegeneration seen in HD. P2X7 and P2Y2 receptors may also play a role in the pathophysiology of HD. Interestingly, nucleotide and nucleoside levels can be altered in animal models of HD and in people with HD. This review presents several studies that describe the relationship between purinergic signaling and HD, and the use of purinoceptors as pharmacological targets and biomarkers of this neurodegenerative disease.
Di Valent Sirna Mediated Silencing Of Msh3 Blocks Somatic Repeat Expansion In Mouse Models Of Huntington’s Disease: Molecular Therapy
Huntington’s disease (HD) is a severe, progressive, and fatal neurodegenerative disease inherited as an autosomal dominant trait (Smith-Dijak et al., 2019; Blumenstock and Dudanova, 2020). It is caused by the expansion of a triple cytosine-adenine-guanine (CAG) repeat in exon 1 of the hunting gene (HTT), located on chromosome 4 (Huntington Disease Functional Research Group, 1993; Capiluppi et al., 2020). This mutation leads to an increased polyglutamine (polyQ) region in the encoded HTT protein (Bailus et al., 2017; Rai et al., 2019). Consequently, the expressed HTT protein is a mutant (mHTT; Cybulska et al., 2020). People with up to 35 CAG repeats are generally considered healthy, while people with 36 to 39 CAG repeats may or may not develop signs and symptoms of HD (Shoulson and Young, 2011; Capiluppi et al., 2020) . More than 50 CAG repeats often cause the disease (Capiluppi et al., 2020). There is an inverse correlation between the number of CAG repeats, the age of onset, and the severity of HD symptoms (Bates et al., 2015; Petersén and Weydt, 2019).
The average prevalence of HD is estimated to be 5 in 100,000 people (Baig et al., 2016; Illarioshkin et al., 2018). HD is characterized by the progression of the neurobehavioral triad of motor dysfunction, cognitive impairment, and cognitive decline (Stahl and Feigin, 2020). Motor dysfunction is divided into two stages: in the first stage, irregular movements occur, called chorea, while in the last stage, voluntary movements are disturbed, causing bradykinesia, dystonia and motor disorders. Neuropsychiatric symptoms seen include depression, apathy, irritability, anxiety and psychosis. Mental disorders often precede motor disorders. Cognitive changes include impairment of attention and visuospatial functions and slowed planning speed. Cognitive decline progresses to dementia (Stahl and Feigin, 2020), and death approaches 15-20 years after the onset of the disease (Blumenstock and Dudanova, 2020). This dysfunction can be attributed to several brain regions that exhibit neurodegeneration, including the cerebral cortex, thalamus, subthalamic nucleus, globus pallidus, substantia nigra, and hypothalamus. However, the hallmark of the disease is called neuronal loss in the striatum (caudate nucleus and putamen; Rubinsztein, 2002; Ramaswamy et al., 2007; Coppen and Roos , 2017). In addition, HD patients may develop metabolic symptoms, including weight loss and cardiovascular and musculoskeletal dysfunction, among others (Blum et al., 2018; Croce and Yamamoto, 2019; Dufour and McBride, 2019).
The striatum is an area responsible for controlling many behaviors, such as movement, adaptive behavior, motivation, and learning (Koch and Raymond, 2019). Two different pathways in the striatum express different neurotransmitters and neuropeptides (Graybiel, 2000). The indirect pathway contains cholinergic interneurons that express dopamine D
R) and enkephalin; projects to the external globus pallidus (Figure 1; GPe; Albin et al., 1989). This method works by inhibiting voluntary movements; as neurons degenerate in the early stages of HD, there is a decrease in D
Review Of Huntington’s Disease: From Basics To Advances In Diagnosis And Treatment
R and, therefore, uncontrolled voluntary movements, which are associated with the symptoms of chorea (Figure 1; Albin et al., 1989; Graybiel, 2000; Koch and Raymond, 2019). The direct pathway characterizes the spiny projection neurons (SPNs) that contain gamma-aminobutyric acid (GABA) that coexists with neuropeptide P and dynorphin. Furthermore, dopamine D
R) projects to the substantia nigra pars reticulata (SNpr) and the internal globus pallidus (GPi), initiating voluntary movements (Figure 1; Albin et al., 1989). In the final stage of HD, in addition to the damaged indirect pathway, degeneration of neurons in the direct pathway occurs, which decreases D.
R and stimulate the cortex. This leads to hypokinetic symptoms, typical of this phase (Figure 1; Albin et al., 1989; Graybiel, 2000; Koch and Raymond, 2019).
Furthermore, neurotransmitters such as dopamine, acetylcholine, glutamate and GABA are involved in motor coordination and changes in their levels cause motor deficits. Evidence has shown changes in these neurotransmitter levels early and late in HD (Spokes, 1980; Kish et al., 1987; Jamwal et al., 2015; Jamwal et al. and Kumar, 2019). These changes in neurotransmitter levels can cause important intracellular biochemical changes, such as reducing the activity of mitochondrial complexes II, III and IV and the levels of adenosine triphosphate (ATP), calcium (Ca).
Huntington Disease: Video, Anatomy & Definition
) overload, excitotoxicity, oxidative stress and mitochondrial dysfunction (Johri et al., 2013; Carmo et al., 2018; Jodeiri Farshbaf and Kiani-Esfahani, 2018), causing cell death (Liot et al. ., 2017). Thus, there is an imbalance in the activity between direct and indirect pathways, resulting in the inappropriate functioning of various neurotransmitter systems in HD. One of the neurotransmitter systems involved in the pathophysiology of HD is the purinergic signal (Burnstock, 2015), associated with the action of nucleotides and nucleosides on P2 and P1 receptors, respectively. Both ATP and adenosine are very important messengers of the purinergic system, which participates in the control of different behaviors (Burnstock, 2015). Adenosine acts as a neuromodulator; in particular, it modulates the dopaminergic and glutamatergic neurotransmission systems (Ferré et al., 2007; Fuxe et al., 2007; Ciruela et al., 2015). Changes in ATP and adenosine levels have been observed in HD (Seong et al., 2005; Kao et al., 2017). Studies have focused on the impact of purinergic signaling in HD, and the development of pharmacological strategies related to the purinergic system as a treatment for HD (Blum et al., 2002; Chou et al., 2005; Simoniin et al., 2013); Villar-Menéndez et al., 2013; Kao et al., 2017). Therefore, this review will discuss the role of purinergic signaling in HD, and the involvement of purinoceptors in the progression of the disease and their importance in the application as pharmacological targets and biomarkers of HD.
Adenosine triphosphate and adenosine are considered the most powerful messengers of purinergic signaling (Burnstock, 1972). Purinergic receptors are classified into P1 and P2 according to their biochemical and pharmacological properties (Burnstock, 2018; Cheffer et al., 2018). P2 receptors are activated by purines [ATP, adenosine diphosphate (ADP)] and pyrimidines (uridine triphosphate, uridine diphosphate) and are classified as P2X and P2Y receptors (Abbracchio and – Burnstock, 1994; Burnstock, 2011). P2X receptors are ATP-gated ion channels that are permeable to sodium (Na
) efflux, which leads to depolarization of the cell membrane. Seven of these receptors (P2X1-7) are expressed by different cells (Burnstock, 2008). P2Y receptors are metabotropic, activated by purines and pyrimidines and are divided into eight receptor subtypes (P2Y
; Burnstock, 2008; Puchałowicz et al., 2014). P1 receptors are metabotropic, choose adenosine and perform physiological actions through four subtypes called A.
A Biological Classification Of Huntington’s Disease: The Integrated Staging System
Protein, inhibits the production of cyclic adenosine monophosphate (cAMP), adenylate cyclase (AC), protein kinase A (PKA) and, consequently, the acquisition of GABA. On the other hand, the
R activates Gs protein, which promotes the production of cAMP, activates AC and PKA, increases GABA secretion. In addition
Nucleotide levels are regulated by ectonucleotidases, a group of enzymes that include nucleotide pyrophosphatases/phosphodiesterases (NPPs), nucleoside triphosphate diphosphohydrolases (NTPDases; CD39), alkaline phosphatase, and ecto-5′-nucleotidase. CD7, CD7, Bonan, CD7; 2012; Zimmermann, 2021). Ectonucleotidases promote extracellular hydrolysis of ATP, producing ADP, adenosine monophosphate (AMP) and adenosine by controlling extracellular concentrations (Burnstock, 1980; Bonan, 2012; Cheffer et al., 2018; Cieslak et al., 2019).
Adenosine, through the action of adenosine deaminase (ADA), can also be released from inosine (Latini and Pedata, 2001). Inosine is phosphorylated by purine nucleoside phosphorylase (PNP) to hypoxanthine and then degraded to a stable product of uric acid (Yegutkin, 2008; Ribeiro et al., 2016). Adenosine levels are also regulated by unidirectional and bidirectional transporters, which allow nucleosides to move between intracellular and extracellular compartments (Fredholm et al., 2001; Ribeiro et al., 2016; Stockwell et al., 2017). Finally, the action of nucleosides is limited either by their conversion to other products of purine catabolism or by resynthesis in nucleotides (Ribeiro et al., 2016).
Timing And Impact Of Psychiatric, Cognitive, And Motor Abnormalities In Huntington Disease
R is the most abundant receptor in the brain – widely expressed in the hippocampus, cerebellum, thalamus, brainstem and spinal cord – while A.
Channel inhibition and neuronal hyperpolarization by regulating the potassium channel. This action leads to a reduction in the release of
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