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Journal of Integrative Neuroscience  2020, Vol. 19 Issue (1): 187-199    DOI: 10.31083/j.jin.2020.01.3
Special Issue: Genetics of neurological diseases
Mini-Review Previous articles | Next articles
Neurodegenerative diseases and cancer: sharing common mechanisms in complex interactions
Natalia González Rojas1, Martin Cesarini1, José Luis Etcheverry1, Gustavo Andrés Da Prat1, 2, Valeria Antico Arciuch3, Emilia Mabel Gatto1, 2, *()
1Instituto Neurociencias Buenos Aires (INEBA), Guardia Vieja 4435, CABA, Argentina
2Sanatorio de la Trinidad Mitre, Bartolomé Mitre 2553, CABA, Argentina
3Conicet, Godoy Cruz 2290, CABA, Argentina
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Several epidemiological studies support low cancer rates in patients with neurodegenerative disorders, including Parkinson's disease, Huntington's disease, and Alzheimer's disease. Different mechanisms were raised as possible causes, from mutated tumor suppressor genes (PARKIN, PINK1) to small interfering RNA based on the CAG trinucleotide repeat expansions located in introns or untranslated regions. However, as every rule has an exception, some tumors have an increased incidence in these neurodegenerative diseases such as breast and skin cancer (melanoma). This mini-review aims to establish the epidemiology between these neurodegenerative disorders and cancer to determine the possible mechanisms involved and therefore set eventual therapeutic applications. According to our findings, we conclude the presence of an inverse relationship among most cancers and the aforementioned neurodegenerative disorders. However, this concept needs to be considered cautiously considering specific genetic and extra-genetic linkage factors for particular tumors.

Key words:  Parkinson’s disease      Huntington’s disease      Alzheimer’s disease      neurodegenerative disorders      cancer      mechanisms     
Submitted:  06 January 2020      Accepted:  27 March 2020      Published:  30 March 2020     
*Corresponding Author(s):  Emilia Mabel Gatto     E-mail:

Cite this article: 

Natalia González Rojas, Martin Cesarini, José Luis Etcheverry, Gustavo Andrés Da Prat, Valeria Antico Arciuch, Emilia Mabel Gatto. Neurodegenerative diseases and cancer: sharing common mechanisms in complex interactions. Journal of Integrative Neuroscience, 2020, 19(1): 187-199.

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Table 1  Observed cancer cases vs. expected ones in an HD population (Coarelli et al., 2017).
Breast 8 14.22
Skin 5 0.98
Bladder 2 4.52
Prostate 1 5.96
Cervix 1 4.48
Figure 1.  Aging results in increased levels of metabolic disturbances, loss of proteostasis, oxidative stress, and DNA damage leading to genomic instability. Many of these aging disturbances are involved in neurodegeneration and cancer and contribute to the development of both disorders.

Figure 2.  Schematic representation of the AMPK-Parkin pathway and the negative regulation of necroptosis and tumorigenesis via RIPK3 inhibition. Parkin reduces cancer-induced inflammation and leads to the inhibitory mechanism of necroptosis. Necrosome complex conformation requires the RIPK1 kinase activation to promote the binding to phosphorylated RIPK3. The complex RIPK1/RIPK3 induces AMPK activation that, in turn, phosphorylates and activates Parkin leading to RIPK3 ubiquitylation. This process inhibits necrosome conformation and prevents necroptosis and cancer-induced inflammation.

Figure 3.  Parkinson’s disease and cancer, Parkin mediated mechanisms. A scheme on the role of PARKIN in the development of cancer. The decreased expression of PARKIN lowers the expression of the tumor suppressor gene PTEN, leading to an increase in proinflammatory interleukins (IL-1b; TNF-a), increasing the rate of cancer development. On the other hand, the overexpression of PARKIN leads to a decreased expression of endothelial growth factor receptor (VEGFR), inducing the stabilization of microtubules and leading to an anti-inflammatory and antitumor effect.

Figure 4.  Overlapping biological pathways of PD and cancer mainly include protein accumulation, mitochondrial damage, oxidative stress response, chronic inflammation, and cell cycle control with flaws in DNA repair. This scheme shows how the three most common genes Parkin, DJ-1, and PINK1 involved in PD lead to dysregulation of both tumor suppressor genes, PTEN, and P53.

Figure 5.  Flow charts of the canonical pathway of mutant Htt to miRNA. In the nucleus, primary microRNAs are cleaved by Drosha complex in precursor microRNA (pre-miRNA), The pre-miRNA is exported to the cytoplasm by Exportin-5. At the cytoplasm, pre-miRNA is processed by Dicer complex into double-stranded loop RNAs, mature microRNA (mature miRNA). The strand with the more unstable 5′-end is selected for loading onto miRNA-induced silencing complex (miRISC). RISC., -bound miRNAs to modulate miRNA activity (degradation and/or translational suppression). Finally, miRNA shows a regulatory role in different pathological pathways involving tumor cells.

Figure 6.  Role of the Huntingtin-associated protein 1 (HAP1) and mutant huntingtin interaction in traffic of organelles and protein regulation. Huntingtin is a scaffold protein with a capacity to bind to a HAP1 protein, which modulates the binding to dynactin or kinesin proteins (microtubule protein complex). The dynactin complex promotes retrograde trafficking, while kinesin promotes anterograde trafficking towards the synaptic area.

Figure 7.  Common pathways to the three neurodegenerative diseases (Huntington’s disease HD, Parkinson’s disease PD and Alzheimer’s disease AD) leading the activation of the P53 gene, with the consequent antioxidant effect and, as a final pathway, the apoptosis of neoplastic cells. P53, a transcriptional factor, has shown multiple functions in the crossroads among cancer and neurodegenerative disorders such as HD, PD, and AD. p53 demonstrates a central role in the balance of cell cycle arrest-DNA repair and programmed death, maintaining a delicate balance between cancer suppressive and age-promoting functions.

Figure 8.  Role of Phosphodiesterase 10A (PDE10A) in the cAMP signaling cascade PDE10A mediated intracellular signaling by hydrolyzing the ATP to the cAMP. Increased levels of cAMP promote activation of protein kinase A (PKA) that, in turn, modulates Dopamine-and cAMP-Regulated Phosphoprotein, Mr 32 kDa (DARPP-32) phosphorylation leading the promotion of neuronal survival by genes regulation.

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