Therapeutic progress in neurodegenerative conditions such as Parkinson’s disease has been hampered by a lack of detailed knowledge of its molecular etiology.The advancements in genetics and genomics have provided fun...Therapeutic progress in neurodegenerative conditions such as Parkinson’s disease has been hampered by a lack of detailed knowledge of its molecular etiology.The advancements in genetics and genomics have provided fundamental insights into specific protein players and the cellular processes involved in the onset of disease.In this respect,the autophagy-lysosome system has emerged in recent years as a strong point of convergence for genetics,genomics,and pathologic indications,spanning both familial and idiopathic Parkinson’s disease.Most,if not all,genes linked to familial disease are involved,in a regulatory capacity,in lysosome function(e.g.,LRRK2,alpha-synuclein,VPS35,Parkin,and PINK1).Moreover,the majority of genomic loci associated with increased risk of idiopathic Parkinson’s cluster in lysosome biology and regulation(GBA as the prime example).Lastly,neuropathologic evidence showed alterations in lysosome markers in autoptic material that,coupled to the alpha-synuclein proteinopathy that defines the disease,strongly indicate an alteration in functionality.In this Brief Review article,I present a personal perspective on the molecular and cellular involvement of lysosome biology in Parkinson’s pathogenesis,aiming at a larger vision on the events underlying the onset of the disease.The attempts at targeting autophagy for therapeutic purposes in Parkinson’s have been mostly aimed at“indiscriminately”enhancing its activity to promote the degradation and elimination of aggregate protein accumulations,such as alpha-synuclein Lewy bodies.However,this approach is based on the assumption that protein pathology is the root cause of disease,while pre-pathology and pre-degeneration dysfunctions have been largely observed in clinical and pre-clinical settings.In addition,it has been reported that unspecific boosting of autophagy can be detrimental.Thus,it is important to understand the mechanisms of specific autophagy forms and,even more,the adjustment of specific lysosome functionalities.Indeed,lysosomes exert fine signaling capacities in addition to their catabolic roles and might participate in the regulation of neuronal and glial cell functions.Here,I discuss hypotheses on these possible mechanisms,their links with etiologic and risk factors for Parkinson’s disease,and how they could be targeted for disease-modifying purposes.展开更多
decisions(Quality Decisions)depend on scientific analysis of data.Data are collected,generally,in two ways:1)one sample of suitable size,2)subsequent samples,at regular intervals of time.Often the data are considered ...decisions(Quality Decisions)depend on scientific analysis of data.Data are collected,generally,in two ways:1)one sample of suitable size,2)subsequent samples,at regular intervals of time.Often the data are considered normally distributed.This is wrong because the data must be analysed according to their distribution:Decisions are different.In several cases the data are exponentially distributed:we see how to scientifically deal with Control Charts(CC)to decide;this is opposite to what gives the T Charts that are claimed to be a good method for dealing with“rare events”:The Minitab Software(19&20&21)for“T Charts”is considered.The author will compare some methods,found in the literature with the author’s Theory RIT(Reliability Integral Theory):We will see various cases found in the literature.Classical Shewhart Control Charts and the TBE(Time Between Events)Control Charts have been considered:it appears that with RIT the future decisions will be both sounder and cheaper,for data is exponentially distributed.The novelty of the paper is in the scientific way of dealing with the Control Charts and their Control Limits,both with normally distributed data and with exponentially distributed data.In this way,a lot of wrong published papers on“Time Between Events”are to be discarded,even if their authors claim“We used Standard Statistical methods,typical in the vast literature of similar papers”.The author had to self-cite because it seems the only one that has been fighting for years for“Papers Quality”;he humbly asked the readers to inform him if some people did the same.展开更多
基金supported by grants from Parkinson Canada,The Weston Brain Foundation and the Euregio Science Fund(to MV).
文摘Therapeutic progress in neurodegenerative conditions such as Parkinson’s disease has been hampered by a lack of detailed knowledge of its molecular etiology.The advancements in genetics and genomics have provided fundamental insights into specific protein players and the cellular processes involved in the onset of disease.In this respect,the autophagy-lysosome system has emerged in recent years as a strong point of convergence for genetics,genomics,and pathologic indications,spanning both familial and idiopathic Parkinson’s disease.Most,if not all,genes linked to familial disease are involved,in a regulatory capacity,in lysosome function(e.g.,LRRK2,alpha-synuclein,VPS35,Parkin,and PINK1).Moreover,the majority of genomic loci associated with increased risk of idiopathic Parkinson’s cluster in lysosome biology and regulation(GBA as the prime example).Lastly,neuropathologic evidence showed alterations in lysosome markers in autoptic material that,coupled to the alpha-synuclein proteinopathy that defines the disease,strongly indicate an alteration in functionality.In this Brief Review article,I present a personal perspective on the molecular and cellular involvement of lysosome biology in Parkinson’s pathogenesis,aiming at a larger vision on the events underlying the onset of the disease.The attempts at targeting autophagy for therapeutic purposes in Parkinson’s have been mostly aimed at“indiscriminately”enhancing its activity to promote the degradation and elimination of aggregate protein accumulations,such as alpha-synuclein Lewy bodies.However,this approach is based on the assumption that protein pathology is the root cause of disease,while pre-pathology and pre-degeneration dysfunctions have been largely observed in clinical and pre-clinical settings.In addition,it has been reported that unspecific boosting of autophagy can be detrimental.Thus,it is important to understand the mechanisms of specific autophagy forms and,even more,the adjustment of specific lysosome functionalities.Indeed,lysosomes exert fine signaling capacities in addition to their catabolic roles and might participate in the regulation of neuronal and glial cell functions.Here,I discuss hypotheses on these possible mechanisms,their links with etiologic and risk factors for Parkinson’s disease,and how they could be targeted for disease-modifying purposes.
文摘decisions(Quality Decisions)depend on scientific analysis of data.Data are collected,generally,in two ways:1)one sample of suitable size,2)subsequent samples,at regular intervals of time.Often the data are considered normally distributed.This is wrong because the data must be analysed according to their distribution:Decisions are different.In several cases the data are exponentially distributed:we see how to scientifically deal with Control Charts(CC)to decide;this is opposite to what gives the T Charts that are claimed to be a good method for dealing with“rare events”:The Minitab Software(19&20&21)for“T Charts”is considered.The author will compare some methods,found in the literature with the author’s Theory RIT(Reliability Integral Theory):We will see various cases found in the literature.Classical Shewhart Control Charts and the TBE(Time Between Events)Control Charts have been considered:it appears that with RIT the future decisions will be both sounder and cheaper,for data is exponentially distributed.The novelty of the paper is in the scientific way of dealing with the Control Charts and their Control Limits,both with normally distributed data and with exponentially distributed data.In this way,a lot of wrong published papers on“Time Between Events”are to be discarded,even if their authors claim“We used Standard Statistical methods,typical in the vast literature of similar papers”.The author had to self-cite because it seems the only one that has been fighting for years for“Papers Quality”;he humbly asked the readers to inform him if some people did the same.
