Maria D. Rodriguez
Investigation of the potential TNT transmission of α-syn between neurons in PD pathogenesis
A.SPECIFIC AIMS
Parkinson’s disease (PD) is defined on a molecular level as an abnormal level of Lewy-body formation, as well as the loss of dopamine-producing neurons in the substantia-nigra in the midbrain . The major protein component found in Lewy-bodies is α-synuclein. This protein is most commonly found in synaptic clefts of neurons in the brain. In familial cases, the excess of these proteins is caused by single-point mutations and gene copy multiplications.
In the past, one of the treatment options being investigated was transplant of embryonic dopaminergic neurons into putamen of humans with PD. Later, autopsy reports …show more content…
This chronic disease targets mostly elder people, with a prevalence of 1.6% in people age 65 and older . Risk factors include aging, genetics and environmental or chemical exposure, but the underlying cause is unknown . PD symptoms severely affect quality of life; non-motor manifestations include anxiety, cognitive impairment, dementia, and autonomic dysfunction (e.g., orthostasis and hyperhidrosis). Motor manifestations include tremor, rigidity, slow movement and stooping. PD is not a cause of death but is associated with increased morbidity and mortality. Although treatment options exist, these can cause serious side effects, and there is no cure for PD. The need for better treatments of PD is necessary, especially since the prevalence is expected to increase significantly as the average lifespan becomes longer (Beitz 2014) . A better understanding of the molecular basis of PD pathogenesis will be useful in the development of better therapies against this idiopathic …show more content…
Ranging from 50 to 200nm in diameter and reaching up to 100µm in length, TNTs are thin actin-containing bridges that allow for communication between cells, transmitting both cytosolic and membrane bound molecules, organelles and even pathogens (Marzo 2012). TNTs are implicated in transmission of prion disease by transferring in vitro endogenous PrPsc from neuronal CAD cells chronically infected with PrPsc to uninfected CAD cells, as well as exogenous, Alexa-labeled PrPsc. Prion disease transmission via TNTs is also implicated due to PrPsc transmission from mouse bone marrow-derived dendritic cells to mouse primary cerebellar granule neurons (CGN) in vitro (Gousset 2009). TNTs are also implicated in Alzheimer’s disease by transfer of amyloid β-EGFP from H2O2 or serum depletion stress-induced TNTs in rat primary hippocampal astrocytes to non-stressed astrocytes, and from stressed to non-stressed rat hippocampus neurons in vitro (Wang 2011). Mutant, GFP-Htt protein was also observed in TNTs in vitro, transferring between primary CGN, suggesting a role for TNT mediated spread of Huntington’s in the brain (Costanzo 2013). In vivo, TNTs have been observed in drosophila and between dendritic cells in mouse cornea (Knopik-Skrocka 2014). It is plausible that TNTs play a role in PD since TNTs are involved in various neurodegenerative disorders, and α-synuclein has been observed in TNTs
Investigation of the potential TNT transmission of α-syn between neurons in PD pathogenesis
A.SPECIFIC AIMS
Parkinson’s disease (PD) is defined on a molecular level as an abnormal level of Lewy-body formation, as well as the loss of dopamine-producing neurons in the substantia-nigra in the midbrain . The major protein component found in Lewy-bodies is α-synuclein. This protein is most commonly found in synaptic clefts of neurons in the brain. In familial cases, the excess of these proteins is caused by single-point mutations and gene copy multiplications.
In the past, one of the treatment options being investigated was transplant of embryonic dopaminergic neurons into putamen of humans with PD. Later, autopsy reports …show more content…
This chronic disease targets mostly elder people, with a prevalence of 1.6% in people age 65 and older . Risk factors include aging, genetics and environmental or chemical exposure, but the underlying cause is unknown . PD symptoms severely affect quality of life; non-motor manifestations include anxiety, cognitive impairment, dementia, and autonomic dysfunction (e.g., orthostasis and hyperhidrosis). Motor manifestations include tremor, rigidity, slow movement and stooping. PD is not a cause of death but is associated with increased morbidity and mortality. Although treatment options exist, these can cause serious side effects, and there is no cure for PD. The need for better treatments of PD is necessary, especially since the prevalence is expected to increase significantly as the average lifespan becomes longer (Beitz 2014) . A better understanding of the molecular basis of PD pathogenesis will be useful in the development of better therapies against this idiopathic …show more content…
Ranging from 50 to 200nm in diameter and reaching up to 100µm in length, TNTs are thin actin-containing bridges that allow for communication between cells, transmitting both cytosolic and membrane bound molecules, organelles and even pathogens (Marzo 2012). TNTs are implicated in transmission of prion disease by transferring in vitro endogenous PrPsc from neuronal CAD cells chronically infected with PrPsc to uninfected CAD cells, as well as exogenous, Alexa-labeled PrPsc. Prion disease transmission via TNTs is also implicated due to PrPsc transmission from mouse bone marrow-derived dendritic cells to mouse primary cerebellar granule neurons (CGN) in vitro (Gousset 2009). TNTs are also implicated in Alzheimer’s disease by transfer of amyloid β-EGFP from H2O2 or serum depletion stress-induced TNTs in rat primary hippocampal astrocytes to non-stressed astrocytes, and from stressed to non-stressed rat hippocampus neurons in vitro (Wang 2011). Mutant, GFP-Htt protein was also observed in TNTs in vitro, transferring between primary CGN, suggesting a role for TNT mediated spread of Huntington’s in the brain (Costanzo 2013). In vivo, TNTs have been observed in drosophila and between dendritic cells in mouse cornea (Knopik-Skrocka 2014). It is plausible that TNTs play a role in PD since TNTs are involved in various neurodegenerative disorders, and α-synuclein has been observed in TNTs